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1
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McDonnell S, MacCormick IJ, Harkin K, Medina RJ, Rodriguez A, Stitt AW. From Bench to Bedside: Unraveling Cerebral Malaria and Malarial Retinopathy by Combining Clinical and Pre-Clinical Perspectives. Curr Eye Res 2025; 50:512-526. [PMID: 39976257 DOI: 10.1080/02713683.2025.2463142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 02/21/2025]
Abstract
Infection with Plasmodium falciparum carries a significant risk of cerebral malaria (CM). Children are particularly susceptible to human CM (HCM) which manifests as an acute neurovascular encephalopathy leading to high levels of mortality. Occurring in parallel with CM, malarial retinopathy (MR) is readily detected on ophthalmoscopy as one or more of: white-centered retinal hemorrhage, retinal whitening, and vessel discoloration. It leads to several distinct types of blood retinal barrier (BRB) breakdown. The precise molecular mechanisms underpinning CM and MR remain ill-defined, but parasitemia is known to drive progressive neurovascular obstruction and inflammation leading to cerebral and retinal edema and ischemia. Extensive clinical studies in patients with CM have shown that retinal examination is a useful approach for understanding pathology and an indicator for risk of mortality and morbidity. Fully understanding the cellular and molecular mechanisms that underpin CM and MR is important for developing new therapeutic approaches and in this regard the murine model of experimental CM (ECM) has proved to offer considerable value. Much is known about brain pathology in this model although much less is understood about the retina. In this review, we seek to evaluate MR in clinical scenarios and make comparisons with the retina from mice with ECM. Through detailed in vivo and post-mortem studies in the mouse and human retina, this review highlights the links between CM and MR and how this will aid our understanding of the disease progression and pathogenesis.
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Affiliation(s)
- Shannon McDonnell
- The Wellcome Wolfson Institute For Experimental Medicine, Queen's University Belfast, Belfast, UK
| | | | - Kevin Harkin
- The Wellcome Wolfson Institute For Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Reinhold J Medina
- Department of Eye and Vision Sciences Institute for Life Course and Medical Science, University of Liverpool, Liverpool, UK
| | - Ana Rodriguez
- Department of Microbiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Alan W Stitt
- The Wellcome Wolfson Institute For Experimental Medicine, Queen's University Belfast, Belfast, UK
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2
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Dinga JN, Ayah F, Anu EF, Qin H, Gamua SD, Tufon AK, Amougou ME, Manyam R. Correlation of Inflammatory Biomarkers and IgG4 Antibodies with Malaria in Cameroon's Buea Municipality Children. Diseases 2025; 13:123. [PMID: 40277833 PMCID: PMC12025989 DOI: 10.3390/diseases13040123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/15/2025] [Accepted: 03/27/2025] [Indexed: 04/26/2025] Open
Abstract
Background: In recent decades, malaria has become a major worldwide public health problem in endemic countries, especially with children below five years. Malaria causes inflammation, and inflammatory biomarkers like α-1-glycoprotein (AGP) and C-reactive protein (CRP) are elevated in serum during malaria. This work aimed at assessing the serum levels of AGP (chronic inflammation) and CRP (acute inflammation) biomarkers and IgG4 and their correlation with malaria in children below five years in the Buea Health District of the South West Region of Cameroon. Methods: This cross-sectional study was carried out between February and April, 2024. AGP and CRP were measured using Q-7plex Human Micronutrient Measurement Kit while IgG4 levels were measured using Enzyme-Linked Immunosorbent Assay with 80 samples. Results: Serum AGP and CRP biomarker levels were significantly higher in malaria-positive children compared to malaria-negative children (p < 0.001 and p < 0.001, respectively). IgG4 levels were high in malaria-negative children (mean OD = 0.51) compared to children infected with the malaria parasite (mean OD = 0.29), in a manner that was statistically significant (p < 0.03). Hemoglobin (Hb) had a strong negative correlation with AGP (-0.62) and CRP (-0.46), meaning that as Hb levels increased, AGP and CRP levels decreased. CRP had a strong positive correlation with both age (0.3) and AGP (0.5), suggesting that as age increased or as AGP levels rose, CRP levels tended to increase as well. Conclusions: This study revealed that malaria causes alterations in the serum levels of AGP, CRP, and IgG4 in children below the age of 5 in the Buea municipality of Cameroon. It impacts immune responses by increasing the level of inflammation biomarkers like AGP and CRP and decreasing IgG4, a marker associated with immune regulation. Thus, this study helps the understanding of the inflammatory nature of malaria and could be expanded to aid in the broader public health efforts to control and prevent malaria, reduce its complications, and improve overall health outcomes in children in the Buea municipality.
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Affiliation(s)
- Jerome Nyhalah Dinga
- Michael Gahnyam Gbeugvat Foundation, Buea 999108, Cameroon
- Biotechnology Unit, University of Buea, Buea 999108, Cameroon
- Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
- African Vaccinology Network, Buea 999108, Cameroon
| | - Flora Ayah
- Buea Regional Hospital, Buea 999108, Cameroon
| | - Emmanuel Fondungallah Anu
- Biotechnology Unit, University of Buea, Buea 999108, Cameroon
- Department of Biochemistry and Molecular Biology, University of Buea, Buea 999108, Cameroon
| | - Haowen Qin
- Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
| | - Stanley Dobgima Gamua
- Michael Gahnyam Gbeugvat Foundation, Buea 999108, Cameroon
- Biotechnology Unit, University of Buea, Buea 999108, Cameroon
- Department of Biochemistry and Molecular Biology, University of Buea, Buea 999108, Cameroon
| | - Anthony Kukwah Tufon
- Buea Regional Hospital, Buea 999108, Cameroon
- Department of Microbiology and Parasitology, University of Buea, Buea 999108, Cameroon
| | | | - Rameshbabu Manyam
- Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
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Bruno F, Georgiou C, Cunningham D, Bett L, Secchi MA, Atkinson S, González Antón S, Birch F, Langhorne J, Lo Celso C. Differential Response and Recovery Dynamics of HSPC Populations Following Plasmodium chabaudi Infection. Int J Mol Sci 2025; 26:2816. [PMID: 40141458 PMCID: PMC11943058 DOI: 10.3390/ijms26062816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.
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Affiliation(s)
- Federica Bruno
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Christiana Georgiou
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | | | - Lucy Bett
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
| | - Marine A. Secchi
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Samantha Atkinson
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Sara González Antón
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Flora Birch
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | | | - Cristina Lo Celso
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
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4
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Ogundeyi KJ, Ajayi AM, Oduyomi OJ, Adeyemo SA, Ologe MO, Ademowo OG. Vitamin C co-administration with artemether-lumefantrine abrogates chronic stress exacerbated Plasmodium berghei-induced sickness behaviour, inflammatory and oxidative stress responses in mice. J Neuroimmunol 2025; 399:578518. [PMID: 39733552 DOI: 10.1016/j.jneuroim.2024.578518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 12/31/2024]
Abstract
This study evaluated the effects of vitamin C and artemether-lumefantrine (AL) on sickness behaviour and oxido-inflammatory response in chronically stressed mice infected with Plasmodium berghei. Sickness behaviour severity was examined with weight and assessment of mice behaviours. Results showed that stress increased parasitaemia in infected mice. Vitamin C co-administration with AL increased parasite clearance over AL alone, and modulated inflammatory cytokines (TNF-α, IL-1β, IL-10, IL-12) and antioxidant parameters in plasma and brain tissue. Conclusively, stress worsens malaria-induced sickness behaviour and up-regulates the inflammatory and oxidative stress response. Co-administration of vitamin C with AL appears to counteract these detrimental effects.
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Affiliation(s)
- Kehinde Joshua Ogundeyi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
| | - Abayomi Mayowa Ajayi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria.
| | - Ololade Justina Oduyomi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
| | - Stella Afolakemi Adeyemo
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
| | - Mary O Ologe
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Ilorin, Kwara-State, Nigeria
| | - Olusegun George Ademowo
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria; Institute of Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, Ibadan, Oyo-State, Nigeria
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5
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Cummings MJ, Lutwama JJ, Owor N, Tomoiaga AS, Ross JE, Muwanga M, Nsereko C, Nayiga I, Kyebambe S, Shinyale J, Ochar T, Nie K, Xie H, Miake-Lye S, Villagomez B, Qi J, Reynolds SJ, Nakibuuka MC, Lu X, Kayiwa J, Haumba M, Nakaseegu J, Che X, Byakika-Kibwika P, Wayengera M, Achan J, Kim-Schulze S, Lipkin WI, O'Donnell MR, Bakamutumaho B. Host Response Stratification in Malarial and Non-malarial Sepsis: A Prospective, Multicenter Analysis From Uganda. Crit Care Med 2025:00003246-990000000-00459. [PMID: 39937058 DOI: 10.1097/ccm.0000000000006591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
OBJECTIVES Globally, the burden of sepsis is highest in malaria endemic areas of sub-Saharan Africa. The influence of malaria on biological heterogeneity inherent to sepsis in this setting is poorly understood. We sought to determine shared and distinct features of the host response in malarial and non-malarial sepsis in sub-Saharan Africa. DESIGN AND SETTING Analysis of Olink proteomic data from prospective observational cohort studies of sepsis conducted at public hospitals in Uganda (discovery cohort [Entebbe, urban], n = 238; validation cohort [Tororo, rural], n = 253). PATIENTS Adults (age ≥ 18 yr) hospitalized with sepsis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The frequency of malaria-associated (malarial) sepsis was 20% in the discovery cohort and 28% in the validation cohort. In both cohorts, a shared host response was predominant, with less than or equal to 8% of proteins differentially expressed (Benjamini-Hochberg-adjusted p ≤ 0.05) between malarial and non-malarial sepsis, after adjustment for demographic variables and HIV and tuberculosis coinfection. In both cohorts, malarial sepsis was associated with increased expression of immunosuppressive proteins (interleukin-10, leukocyte immunoglobulin-like receptor B1, killer cell immunoglobulin-like receptor 3DL1), including those associated with Tcell exhaustion and apoptosis (lymphocyte activation gene 3, T cell immunoglobulin and mucin domain containing 4). A classifier model including these immunosuppressive proteins showed reasonable discrimination (area under the receiver operating characteristic curves, 0.73 [95% CI, 0.65-0.81] and 0.72 [0.65-0.79]) and calibration (Brier scores 0.14 and 0.18) for stratification of malarial sepsis in the discovery and validation cohorts, respectively. CONCLUSIONS Host responses are largely conserved in malarial and non-malarial sepsis but may be distinguished by a signature of relative immunosuppression in the former. Further investigations are needed to differentiate mechanisms of malarial and non-malarial sepsis, with the goal of informing pathogen-stratified and pathogen-agnostic treatment strategies.
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Affiliation(s)
- Matthew J Cummings
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
| | - Julius J Lutwama
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Nicholas Owor
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Alin S Tomoiaga
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Accounting, Business Analytics, Computer Information Systems, and Law, Manhattan College, Bronx, NY
| | - Jesse E Ross
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Moses Muwanga
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | | | - Irene Nayiga
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Stephen Kyebambe
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Joseph Shinyale
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Thomas Ochar
- Tororo General Hospital, Ministry of Health, Tororo, Uganda
| | - Kai Nie
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Hui Xie
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Sam Miake-Lye
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Bryan Villagomez
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jingjing Qi
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Steven J Reynolds
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
- Rakai Health Sciences Program, Kalisizo, Uganda
| | | | - Xuan Lu
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - John Kayiwa
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Mercy Haumba
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Joweria Nakaseegu
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Xiaoyu Che
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | | | - Misaki Wayengera
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Jane Achan
- Global Technical Team, Malaria Consortium, London, United Kingdom
| | - Seunghee Kim-Schulze
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Max R O'Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Barnabas Bakamutumaho
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
- Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda
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6
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Chen J, Bai Y, He X, Xiao W, Chen L, Wong YK, Wang C, Gao P, Cheng G, Xu L, Yang C, Liao F, Han G, Sun J, Xu C, Wang J. The spatiotemporal transcriptional profiling of murine brain during cerebral malaria progression and after artemisinin treatment. Nat Commun 2025; 16:1540. [PMID: 39934099 PMCID: PMC11814382 DOI: 10.1038/s41467-024-52223-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 08/28/2024] [Indexed: 02/13/2025] Open
Abstract
Cerebral malaria (CM) is a severe encephalopathy caused by Plasmodium parasite infection, resulting in thousands of annual deaths and neuro-cognitive sequelae even after anti-malarial drugs treatment. Despite efforts to dissect the mechanism, the cellular transcriptomic reprogramming within the spatial context remains elusive. Here, we constructed single-cell and spatial transcriptome atlases of experimental CM (ECM) male murine brain tissues with or without artesunate (ART) treatment. We identified activated inflammatory endothelial cells during ECM, characterized by a disrupted blood-brain barrier, increased antigen presentation, and leukocyte adhesion. We also observed that inflammatory microglia enhance antigen presentation pathway such as MHC-I to CD8+ cytotoxic T cells. The latter underwent an inflammatory state transition with up-regulated cytokine expression and cytotoxic activity. Multi-omics analysis revealed that the activated interferon-gamma response of injured neurons during ECM and persisted after ART treatment. Overall, our research provides valuable resources for understanding malaria parasite-host interaction mechanisms and adjuvant therapy development.
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Affiliation(s)
- Jiayun Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Yunmeng Bai
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Xueling He
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Wei Xiao
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
- Department of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Lina Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yin Kwan Wong
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Chen Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Peng Gao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China
| | - Guangqing Cheng
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Liting Xu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chuanbin Yang
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Fulong Liao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Guang Han
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China
| | - Jichao Sun
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Chengchao Xu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Jigang Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
- Department of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China.
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7
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Céspedes N, Tsolis RM, Piliponsky AM, Luckhart S. The type 2 immune response in gut homeostasis and parasite transmission in malaria. Trends Parasitol 2025; 41:38-51. [PMID: 39658487 DOI: 10.1016/j.pt.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/18/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024]
Abstract
Malaria predisposes to concomitant bacteremia, resulting in increased mortality risk. Previous studies indicated that malaria causes structural changes in the intestine, induces tolerogenic immune responses, inhibits neutrophil recruitment, suppresses innate synthesis of IFN-γ, dysregulates mast cells (MCs) and basophils, and induces Th2-type immune responses. These can reduce parasite control while increasing enteropathogenic dissemination. Moreover, there is growing evidence that Th2 immunity, while protecting the host from overwhelming inflammation, may also contribute to increased parasite transmission. This review explores the roles of the regulatory immune response in bacterial coinfections and parasite transmission in malaria.
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Affiliation(s)
- Nora Céspedes
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID, USA.
| | - Renée M Tsolis
- Department of Medical Microbiology and Immunology, University of California-Davis, Davis, CA, USA
| | - Adrian M Piliponsky
- Department of Pediatrics and Department of Pathology, Seattle Children's Research Institute, Seattle, WA, USA
| | - Shirley Luckhart
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID, USA; Department of Biological Sciences, University of Idaho, Moscow, ID, USA
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8
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Moreira ET, Lourenço MP, Cunha-Fernandes T, Silva TI, Siqueira LD, Castro-Faria-Neto HC, Reis PA. Minocycline inhibits microglial activation in the CA1 hippocampal region and prevents long-term cognitive sequel after experimental cerebral malaria. J Neuroimmunol 2024; 397:578480. [PMID: 39504755 DOI: 10.1016/j.jneuroim.2024.578480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/24/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024]
Abstract
Cerebral malaria is the worst complication of malaria infection, has a high mortality rate, and may cause different neurodysfunctions, including cognitive decline. Neuroinflammation is an important cause of cognitive damage in neurodegenerative diseases, and microglial cells can be activated in a disease-associated profile leading to tissue damage and neuronal death. Here, we demonstrated that treatment with minocycline reduced blood-brain barrier breakdown and modulated ICAM1 mRNA expression; reduced proinflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, and IL-6; and prevented long-term cognitive decline in contextual and aversive memory tasks. Taken together, our data suggest that microglial cells are activated during experimental cerebral malaria, leading to neuroinflammatory events that end up in cognitive damage. In addition, pharmacological modulation of microglial activation, by drugs such as minocycline may be an important therapeutic strategy in the prevention of long-term memory impairment.
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Affiliation(s)
- E T Moreira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Universidade Cruzeiro do Sul, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - M P Lourenço
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T Cunha-Fernandes
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T I Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - L D Siqueira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - H C Castro-Faria-Neto
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - P A Reis
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil
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9
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García-Flores OR, Avilés-Ramírez ME, Castillo-Paniagua SV, Pérez-Jiménez EM, Gasca-Aldama JC, Soto-Abraham MV, Bravata-Alcántara JC, Bello-López JM, Piccoli GB, Vásquez-Jiménez E. Kidney involvement in Plasmodium falciparum infection in a pregnant patient. Malar J 2024; 23:345. [PMID: 39558378 PMCID: PMC11572360 DOI: 10.1186/s12936-024-05182-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/08/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND The course of kidney function and outcomes of severe malaria infection in pregnant women is poorly understood. The indications for renal replacement therapy in pregnant patients with AKI are similar to the general population. This is the case of a pregnant patient with severe Plasmodium falciparum infection that caused cerebral malaria, acute kidney injury (AKI) who required renal replacement therapy and kidney biopsy during her hospitalization. CASE PRESENTATION A 29-year-old pregnant woman from Equatorial Guinea was admitted to the hospital with haemolytic anaemia, hyperbilirubinaemia and thrombocytopenia. During hospitalization, a thick blood smear was performed where parasitaemia by P. falciparum were observed and confirmed by real-time PCR assay. The patient developed cerebral malaria secondary to an ischaemic-type cerebral vascular event, hypotension and severe. After confirming diagnosis of P. falciparum infection, artesunate, artemether/lumefantrine and primaquine were started. Kidney biopsy revealed an active tubulointerstitial nephritis with acute tubular lesion and pigment tubulopathy with negative immunofluorescence. After CVVHDF, the patient received intermittent haemodialysis until the recovery of kidney function. After discharge, follow-up was carried until the successful resolution of the pregnancy by cesarean delivery and not shown deterioration in kidney function or proteinuria. CONCLUSION In this case, intensive dialysis was started and dialysis intensity progressively reduced when kidney function improved. Due to the evolution of kidney function, a kidney biopsy was performed which showed tubulointerstitial nephritis as a manifestation of the infection. While the kidney biopsy was of interest for discriminating between tubular and glomerular involvement, the availability of placental biomarkers (sflt1-PlGF) would have been of help for ruling out preeclampsia and placental damage. The multidisciplinary approach to AKI during pregnancy should be the rule, with diligent care of maternal-fetal well-being during pregnancy and monitoring of kidney function after delivery.
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Affiliation(s)
- Octavio René García-Flores
- Department of Nephrology, Hospital Juárez de México, Av Instituto Politécnico Nacional 5160, 07760, Mexico City, Mexico
| | - Mayra Eugenia Avilés-Ramírez
- Department of Nephrology, Hospital Juárez de México, Av Instituto Politécnico Nacional 5160, 07760, Mexico City, Mexico
| | | | - Edgar Misael Pérez-Jiménez
- Department of Nephrology, Hospital Juárez de México, Av Instituto Politécnico Nacional 5160, 07760, Mexico City, Mexico
| | | | | | | | | | | | - Enzo Vásquez-Jiménez
- Department of Nephrology, Hospital Juárez de México, Av Instituto Politécnico Nacional 5160, 07760, Mexico City, Mexico.
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10
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Muchaamba G, Venugopal K, Gächter B, Vogler B, Hetzel U, Albini S, Marti M. Avian malaria in a feral-pet pigeon: a case report. Malar J 2024; 23:294. [PMID: 39358742 PMCID: PMC11446001 DOI: 10.1186/s12936-024-05116-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Avian malaria is caused by diverse parasite species of the genus Plasmodium, and it affects various bird species. The occurrence of this disease in some wild bird species is sparsely documented due to the scarce availability of samples. Hence the pathogenicity in some hosts is not completely known. In addition, feral birds may act as reservoirs bridging the transmission cycle from wild migratory birds to domestic and zoo-kept bird species. CASE PRESENTATION An owner of pigeons adopted a feral pigeon (Columba livia forma domestica) and housed it together with his other pet-pigeons. The bird died unexpectedly a few weeks after a surgical procedure and necropsy revealed a severely anaemic carcass, with pale organs and hydropericardium. Histopathologic analysis revealed inflammatory infiltrates in the lung and liver, and monocytes and Kupffer cells contained haemozoin pigment indicative of phagocytosis of Plasmodium-infected erythrocytes. A high erythrocytic infection rate of 18% was evident in tissues and blood vessels in various organs. Furthermore, the thyroid had masses classified as thyroid carcinomas. Immunohistochemistry with anti- Plasmodium falciparum HSP70 antibody revealed positive signals in erythrocytes and intravascular leucocytes. Further microscopy analysis using a Hemacolor-stained impression smear revealed a high parasitaemia with an asynchronous infection showing all erythrocytic stages. Molecular diagnosis by PCR identified Plasmodium relictum, lineage GRW11 as the aetiological agent. The bird presented died most likely due to an acute infection as evidenced by the high blood parasitaemia, leading to major erythrocyte destruction. Further analyses of feral pigeons (n = 22) did not reveal any additional cases of Plasmodium infections. CONCLUSION This study reports the first mortality associated with P. relictum lineage GRW11. The study supports previous studies, suggesting that Plasmodium infections are not frequent in pigeons. Host conditions like immunosuppression due to the tumour may have influenced the infection outcome in this fatal case. Use of anti-P. falciparum HSP70 antibody for detection of P. relictum antigens for immune assays in blood and tissue samples will be a useful tool for future studies.
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Affiliation(s)
- Gillian Muchaamba
- Institute of Parasitology, Vetsuisse and Medical Faculty, University of Zurich, Zurich, Switzerland
- Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, UK
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Kannan Venugopal
- Institute of Parasitology, Vetsuisse and Medical Faculty, University of Zurich, Zurich, Switzerland
- Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, UK
| | - Bettina Gächter
- Section for Poultry and Rabbit Diseases (NRGK), Institute for Food Safety and Hygiene, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Barbara Vogler
- Section for Poultry and Rabbit Diseases (NRGK), Institute for Food Safety and Hygiene, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Udo Hetzel
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Sarah Albini
- Section for Poultry and Rabbit Diseases (NRGK), Institute for Food Safety and Hygiene, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Matthias Marti
- Institute of Parasitology, Vetsuisse and Medical Faculty, University of Zurich, Zurich, Switzerland.
- Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, UK.
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11
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Ekemen S, Nalcaci M, Toz S, Sanjoba C, Demirkesen C, Cetin ED, Tecimer T, Yildiz P, Gursel M, Ince U, Ozbel Y, Coban C. Diagnostic challenges in cutaneous leishmaniasis due to atypical Leishmania infantum: pathologists' insights from re-emergence zones. Front Med (Lausanne) 2024; 11:1453211. [PMID: 39328317 PMCID: PMC11425964 DOI: 10.3389/fmed.2024.1453211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 09/02/2024] [Indexed: 09/28/2024] Open
Abstract
Background Leishmaniasis, a parasitic infection affecting both humans and animals, is increasingly spreading across Mediterranean and European regions, largely driven by human migration and environmental changes. In countries like Türkiye and across Europe, which have seen large influxes of migrants, the incidence of cutaneous leishmaniasis (CL) is rising, with cases now appearing in cities where the disease was previously undocumented. In these previously non-endemic areas, physicians unfamiliar with the characteristic lesions may misdiagnose CL, particularly in cases with only cutaneous manifestations. This study aims to evaluate the impact of re-emerging CL on the routine diagnostic practices of pathologists in Türkiye, by retrospectively reviewing cases. Methods We conducted a retrospective analysis of CL cases diagnosed between 2013 and 2022 at a single pathology center in Türkiye, covering multiple provinces. Twelve cases of CL were identified and analyzed based on clinical presentation, pre-diagnosis, histopathological findings, and molecular diagnostics. DNA extraction and PCR were performed on paraffin-embedded tissue samples to identify the Leishmania species involved. Results Out of the twelve CL cases reviewed, seven exhibited morphological findings strongly suggestive of CL (MFSS of CL), warranting further microbiological evaluation. All patients presented with non-healing skin lesions characterized by central ulceration, crater-like formations, or papulonodular lesions. Notably, CL was included in the clinical pre-diagnosis in only 58.3% of cases, while it was not considered in the remaining 41.7% of cases. Clinicians initially pre-diagnosed skin tumors in six cases (50%), four of which led to wide surgical excision. Histopathological examination in all cases revealed chronic or mixed (acute/chronic) inflammation, predominantly rich in histiocytes. To further investigate the role of Leishmania species in the pre-diagnosis, DNA extraction and PCR were performed on paraffin-embedded tissue samples, identifying L. infantum as the causative agent in 10 cases and L. major in two cases. Notably, L. infantum was the causative agent in all five cases initially misdiagnosed as skin tumors, which were also associated with a granulomatous type of chronic inflammation.
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Affiliation(s)
- Suheyla Ekemen
- Vocational School of Health Services, Acibadem University, Istanbul, Türkiye
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Japan Science and Technology Research Partnership for Sustainable Development (SATREPS) One Health Project, Tokyo, Japan
| | - Muhammed Nalcaci
- Department of Parasitology, Ege University School of Medicine, Izmir, Türkiye
| | - Seray Toz
- Japan Science and Technology Research Partnership for Sustainable Development (SATREPS) One Health Project, Tokyo, Japan
- Department of Parasitology, Ege University School of Medicine, Izmir, Türkiye
| | - Chizu Sanjoba
- Japan Science and Technology Research Partnership for Sustainable Development (SATREPS) One Health Project, Tokyo, Japan
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Cuyan Demirkesen
- Department of Pathology, Acibadem University School of Medicine, Istanbul, Türkiye
| | - Emel D Cetin
- Acibadem Central Pathology Laboratory, Istanbul, Türkiye
| | - Tulay Tecimer
- Acibadem Central Pathology Laboratory, Istanbul, Türkiye
| | - Pelin Yildiz
- Department of Pathology, Acibadem University School of Medicine, Istanbul, Türkiye
| | - Mayda Gursel
- Izmir Biomedicine and Genome Center, Basic and Translational Research Program, Izmir, Türkiye
| | - Umit Ince
- Vocational School of Health Services, Acibadem University, Istanbul, Türkiye
- Department of Pathology, Acibadem University School of Medicine, Istanbul, Türkiye
- Acibadem Central Pathology Laboratory, Istanbul, Türkiye
| | - Yusuf Ozbel
- Japan Science and Technology Research Partnership for Sustainable Development (SATREPS) One Health Project, Tokyo, Japan
- Department of Parasitology, Ege University School of Medicine, Izmir, Türkiye
| | - Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Japan Science and Technology Research Partnership for Sustainable Development (SATREPS) One Health Project, Tokyo, Japan
- International Vaccine Design Center, Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo, Japan
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12
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Alshaweesh J, Dash R, Lee MSJ, Kahyaoglu P, Erci E, Xu M, Matsuo-Dapaah J, Del Rosario Zorrilla C, Aykac K, Ekemen S, Kobiyama K, Ishii KJ, Coban C. MyD88 in osteoclast and osteoblast lineages differentially controls bone remodeling in homeostasis and malaria. Int Immunol 2024; 36:451-464. [PMID: 38642134 PMCID: PMC11319481 DOI: 10.1093/intimm/dxae023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/16/2024] [Indexed: 04/22/2024] Open
Abstract
Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography to that of controls after Plasmodium yoelii non-lethal infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC, precursors resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, insulin-like growth factor-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions.
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Affiliation(s)
- Jalal Alshaweesh
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- International Vaccine Design Center, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo 108-8639, Japan
| | - Rashmi Dash
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- Department of Computational Biology and Medical Science (CBMS), Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan
| | - Michelle S J Lee
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- International Vaccine Design Center, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo 108-8639, Japan
| | - Pinar Kahyaoglu
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
- Department of Paediatrics, Hacettepe University School of Medicine, Ankara 06100, Turkey
| | - Ece Erci
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
- Department of Paediatrics, Hacettepe University School of Medicine, Ankara 06100, Turkey
| | - Mengling Xu
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- Department of Computational Biology and Medical Science (CBMS), Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan
| | - Julia Matsuo-Dapaah
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Camila Del Rosario Zorrilla
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- Department of Computational Biology and Medical Science (CBMS), Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan
| | - Kubra Aykac
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
- Department of Paediatrics, Hacettepe University School of Medicine, Ankara 06100, Turkey
- Ministry of Health University, Ankara Education and Research Hospital, Paediatric Infectious Diseases Unit, Ankara 06230, Turkey
| | - Suheyla Ekemen
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
| | - Kouji Kobiyama
- International Vaccine Design Center, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo 108-8639, Japan
- Division of Vaccine Science, Department of Microbiology and Immunology, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
| | - Ken J Ishii
- International Vaccine Design Center, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo 108-8639, Japan
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
- Division of Vaccine Science, Department of Microbiology and Immunology, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
| | - Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo 108-8639, Japan
- International Vaccine Design Center, IMSUT, The University of Tokyo, Tokyo 108-8639, Japan
- The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo 108-8639, Japan
- Department of Computational Biology and Medical Science (CBMS), Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
- Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
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Carvalho Cabral P, Richard VR, Borchers CH, Olivier M, Cermakian N. Circadian Control of the Response of Macrophages to Plasmodium Spp.-Infected Red Blood Cells. Immunohorizons 2024; 8:442-456. [PMID: 38916585 PMCID: PMC11220744 DOI: 10.4049/immunohorizons.2400021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/23/2024] [Indexed: 06/26/2024] Open
Abstract
Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.
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Affiliation(s)
| | - Vincent R. Richard
- Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada
| | - Christoph H. Borchers
- Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada
| | - Martin Olivier
- Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Nicolas Cermakian
- Douglas Research Centre, McGill University, Montreal, Quebec, Canada
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14
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Carvalho Cabral P, Weinerman J, Olivier M, Cermakian N. Time of day and circadian disruption influence host response and parasite growth in a mouse model of cerebral malaria. iScience 2024; 27:109684. [PMID: 38680656 PMCID: PMC11053314 DOI: 10.1016/j.isci.2024.109684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/20/2023] [Accepted: 04/04/2024] [Indexed: 05/01/2024] Open
Abstract
Malaria is a disease caused by infection with parasite Plasmodium spp. We studied the circadian regulation of host responses to the parasite, in a mouse model of cerebral malaria. The course of the disease was markedly affected by time of infection, with decreased parasitemia and increased inflammation upon infection in the middle of the night. At this time, there were fewer reticulocytes, which are target cells of the parasites. We next investigated the effects of desynchronization of host clocks on the infection: after 10 weeks of recurrent jet lags, mice showed decreased parasite growth and lack of parasite load rhythmicity, paralleled by a loss of glucose rhythm. Accordingly, disrupting host metabolic rhythms impacted parasite load rhythmicity. In summary, our findings of a circadian modulation of malaria parasite growth and infection shed light on aspects of the disease relevant to human malaria and could contribute to new therapeutic or prophylactic measures.
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Affiliation(s)
- Priscilla Carvalho Cabral
- Douglas Research Centre, McGill University, Montréal, QC H4H 1R3, Canada
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
| | - Joelle Weinerman
- Douglas Research Centre, McGill University, Montréal, QC H4H 1R3, Canada
| | - Martin Olivier
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Nicolas Cermakian
- Douglas Research Centre, McGill University, Montréal, QC H4H 1R3, Canada
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15
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Alves-Rosa MF, Tayler NM, Dorta D, Coronado LM, Spadafora C. P. falciparum Invasion and Erythrocyte Aging. Cells 2024; 13:334. [PMID: 38391947 PMCID: PMC10887143 DOI: 10.3390/cells13040334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Plasmodium parasites need to find red blood cells (RBCs) that, on the one hand, expose receptors for the pathogen ligands and, on the other hand, maintain the right geometry to facilitate merozoite attachment and entry into the red blood cell. Both characteristics change with the maturation of erythrocytes. Some Plasmodia prefer younger vs. older erythrocytes. How does the life evolution of the RBC affect the invasion of the parasite? What happens when the RBC ages? In this review, we present what is known up until now.
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Affiliation(s)
| | | | | | | | - Carmenza Spadafora
- Center of Cellular and Molecular Biology of Diseases, Instituto de Investigaciones Científicas y Servicio de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama City 0843-01103, Panama; (M.F.A.-R.); (N.M.T.); (D.D.); (L.M.C.)
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16
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Xu R, Zhang S, Wang P, Zhang R, Lin P, Wang Y, Gao L, Wei H, Zhang X, Ling D, Yan X, Fan K. Nanozyme-based strategies for efficient theranostics of brain diseases. Coord Chem Rev 2024; 501:215519. [DOI: 10.1016/j.ccr.2023.215519] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Philothra BD, Alona I, Situmorang E, Limbardon P, Salsalina VG. Treatment-seeking behavior for malaria among communities in Indonesia: A systematic review. NARRA J 2023; 3:e428. [PMID: 38455613 PMCID: PMC10919435 DOI: 10.52225/narra.v3i3.428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/06/2023] [Indexed: 03/09/2024]
Abstract
Indonesia stands as one of the nine malaria-endemic countries in Southeast Asia with a total of 443,530 cases in 2022. Eastern Indonesia is listed as an area with high malaria endemicity and the Indonesian government has set a target of eliminating malaria by 2030. From 2010 to 2014, the number of malaria cases decreased but stagnated until 2020 and have continued to increase. Stagnation may occur as a result of many non-medical treatment-seeking behaviors. The aim of this systematic review was to provide a summary and overview of malaria treatment-seeking behavior among communities in several regions in Indonesia. The searches were conducted through four databases (Cochrane, PubMed, Google Scholar, and ScienceDirect) using medical subject headings (MeSH) "treatment-seeking behavior" OR "health-seeking behavior" AND "malaria" AND "Indonesia". This systematic review was limited to studies conducted in Indonesia that were published between 2013 and 2023 using either a quantitative or qualitative approach. Out of 2831 studies, a total of thirteen studies were included. The pattern of seeking malaria treatment varied between doing nothing or no action, self-treatment (purchasing drugs at pharmacies and consuming leftover medicines), traditional medicine, and medical treatment (public health facilities or malaria control clinics). Those behaviors are attributed to education level, socioeconomic level, occupation, distance from home to health facilities, geographical conditions, and people's perceptions of malaria and antimalarial medicines. There is still a range of malaria treatment-seeking behavior outside of recommended medical treatment in communities in several regions in Indonesia. The phenomenon of medical pluralism and syncretism requires approaches from various sectors in order to achieve a malaria-free Indonesia by 2030.
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Affiliation(s)
| | - Ivana Alona
- Departement of Public Health/Community Medicine/Preventive Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Directorate of Education, Training, Research, and Collaboration of Prof. dr. Chairuddin P. Lubis Universitas Sumatera Utara Hospital, Universitas Sumatera Utara, Medan, Indonesia
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Król G, Fortunka K, Majchrzak M, Piktel E, Paprocka P, Mańkowska A, Lesiak A, Karasiński M, Strzelecka A, Durnaś B, Bucki R. Metallic Nanoparticles and Core-Shell Nanosystems in the Treatment, Diagnosis, and Prevention of Parasitic Diseases. Pathogens 2023; 12:838. [PMID: 37375528 DOI: 10.3390/pathogens12060838] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
The usage of nanotechnology in the fight against parasitic diseases is in the early stages of development, but it brings hopes that this new field will provide a solution to target the early stages of parasitosis, compensate for the lack of vaccines for most parasitic diseases, and also provide new treatment options for diseases in which parasites show increased resistance to current drugs. The huge physicochemical diversity of nanomaterials developed so far, mainly for antibacterial and anti-cancer therapies, requires additional studies to determine their antiparasitic potential. When designing metallic nanoparticles (MeNPs) and specific nanosystems, such as complexes of MeNPs, with the shell of attached drugs, several physicochemical properties need to be considered. The most important are: size, shape, surface charge, type of surfactants that control their dispersion, and shell molecules that should assure specific molecular interaction with targeted molecules of parasites' cells. Therefore, it can be expected that the development of antiparasitic drugs using strategies provided by nanotechnology and the use of nanomaterials for diagnostic purposes will soon provide new and effective methods of antiparasitic therapy and effective diagnostic tools that will improve the prevention and reduce the morbidity and mortality caused by these diseases.
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Affiliation(s)
- Grzegorz Król
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Kamila Fortunka
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Michał Majchrzak
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Ewelina Piktel
- Independent Laboratory of Nanomedicine, Medical University of Białystok, Mickiewicza 2B, 15-222 Białystok, Poland
| | - Paulina Paprocka
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Angelika Mańkowska
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Agata Lesiak
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Maciej Karasiński
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2C, 15-222 Białystok, Poland
| | - Agnieszka Strzelecka
- Department of Public Health , Institute of Health Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Bonita Durnaś
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Robert Bucki
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University, IX Wieków Kielc 19A, 25-317 Kielce, Poland
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2C, 15-222 Białystok, Poland
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Vialard F, Allaeys I, Dong G, Phan MP, Singh U, Hébert MJ, Dieudé M, Langlais D, Boilard E, Labbé DP, Olivier M. Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression. Front Immunol 2023; 14:1128466. [PMID: 37350957 PMCID: PMC10283000 DOI: 10.3389/fimmu.2023.1128466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
Introduction Most studies using murine disease models are conducted at housing temperatures (20 - 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 - 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted experiments to determine: (1) the inflammatory response to malarial agents injection in a peritonitis model and (2) disease progression in PbA-infected mice at TT compared to ST. Methods In one study, acclimatized mice were injected intraperitoneally with native hemozoin (nHZ) or Leishmania at TT (28 - 31°C) or ST, and immune cells, cytokine, and extracellular vesicle (EV) profiles were determined from the peritoneal cavity (PEC) fluid. In another study, PbA-infected mice were monitored until end-point (i.e. experimental malaria score ≥4). Results We found that Leishmania injection resulted in decreased cell recruitment and higher phagocytosis of nHZ in mice housed at TT. We found 398 upregulated and 293 downregulated proinflammatory genes in mice injected with nHZ, at both temperatures. We report the presence of host-derived EVs never reported before in a murine parasitic murine model at both temperatures. We observed metabolic changes in mice housed at TT, but these did not result to noticeable changes in disease progression compared to ST. Discussion To our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. We found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations.
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Affiliation(s)
- Fiorella Vialard
- Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Isabelle Allaeys
- Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada
| | - George Dong
- Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Minh Phuong Phan
- Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Urvashi Singh
- Department of Human Genetics, McGill University Genome Centre, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Marie Josée Hébert
- Centre de Recherche, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Mélanie Dieudé
- Centre de Recherche, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
- Département Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - David Langlais
- Department of Human Genetics, McGill University Genome Centre, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Eric Boilard
- Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada
| | - David P. Labbé
- Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Division of Urology, Department of Surgery, McGill University, Montréal, QC, Canada
| | - Martin Olivier
- Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
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20
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Wu X, Dayanand KK, Thylur Puttalingaiah R, Punnath K, Norbury CC, Gowda DC. Different TLR signaling pathways drive pathology in experimental cerebral malaria vs. malaria-driven liver and lung pathology. J Leukoc Biol 2023; 113:471-488. [PMID: 36977632 DOI: 10.1093/jleuko/qiad021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 02/08/2023] [Accepted: 02/15/2023] [Indexed: 03/30/2023] Open
Abstract
Malaria infection causes multiple organ-specific lethal pathologies, including cerebral malaria, and severe liver and lung pathologies by inducing strong inflammatory responses. Gene polymorphism studies suggest that TLR4 and TLR2 contribute to severe malaria, but the roles of these signaling molecules in malaria pathogenesis remain incompletely understood. We hypothesize that danger-associated molecular patterns produced in response to malaria activate TLR2 and TLR4 signaling and contribute to liver and lung pathologies. By using a mouse model of Plasmodium berghei NK65 infection, we show that the combined TLR2 and TLR4 signaling contributes to malaria liver and lung pathologies and mortality. Macrophages, neutrophils, natural killer cells, and T cells infiltrate to the livers and lungs of infected wild-type mice more than TLR2,4-/- mice. Additionally, endothelial barrier disruption, tissue necrosis, and hemorrhage were higher in the livers and lungs of infected wild-type mice than in those of TLR2,4-/- mice. Consistent with these results, the levels of chemokine production, chemokine receptor expression, and liver and lung pathologic markers were higher in infected wild-type mice than in TLR2,4-/- mice. In addition, the levels of HMGB1, a potent TLR2- and TLR4-activating danger-associated molecular pattern, were higher in livers and lungs of wild-type mice than TLR2,4-/- mice. Treatment with glycyrrhizin, an immunomodulatory agent known to inhibit HMGB1 activity, markedly reduced mortality in wild-type mice. These results suggest that TLR2 and TLR4 activation by HMGB1 and possibly other endogenously produced danger-associated molecular patterns contribute to malaria liver and lung injury via signaling mechanisms distinct from those involved in cerebral malaria pathogenesis.
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Affiliation(s)
- Xianzhu Wu
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - Kiran K Dayanand
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - Ramesh Thylur Puttalingaiah
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - Kishore Punnath
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - Christopher C Norbury
- Departments of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - D Channe Gowda
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
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Cell-Membrane-Coated Nanoparticles for Targeted Drug Delivery to the Brain for the Treatment of Neurological Diseases. Pharmaceutics 2023; 15:pharmaceutics15020621. [PMID: 36839943 PMCID: PMC9960717 DOI: 10.3390/pharmaceutics15020621] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/21/2023] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
Neurological diseases (NDs) are a significant cause of disability and death in the global population. However, effective treatments still need to be improved for most NDs. In recent years, cell-membrane-coated nanoparticles (CMCNPs) as drug-targeting delivery systems have become a research hotspot. Such a membrane-derived, nano drug-delivery system not only contributes to avoiding immune clearance but also endows nanoparticles (NPs) with various cellular and functional mimicries. This review article first provides an overview of the function and mechanism of single/hybrid cell-membrane-derived NPs. Then, we highlight the application and safety of CMCNPs in NDs. Finally, we discuss the challenges and opportunities in the field.
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22
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Disulfide bond and crosslinking analyses reveal inter-domain interactions that contribute to the rigidity of placental malaria VAR2CSA structure and formation of CSA binding channel. Int J Biol Macromol 2023; 226:143-158. [PMID: 36470436 DOI: 10.1016/j.ijbiomac.2022.11.258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/15/2022] [Accepted: 11/24/2022] [Indexed: 12/11/2022]
Abstract
VAR2CSA, a multidomain Plasmodium falciparum protein, mediates the adherence of parasite-infected red blood cells to chondroitin 4-sulfate (C4S) in the placenta, contributing to placental malaria. Therefore, detailed understanding of VAR2CSA structure likely help developing strategies to treat placental malaria. The VAR2CSA ectodomain consists of an N-terminal segment (NTS), six Duffy binding-like (DBL) domains, and three interdomains (IDs) present in sequence NTS-DBL1x-ID1-DBL2x-ID2-DBL3x-DBL4ε-ID3-DBL5ε-DBL6ε. Recent electron microscopy studies showed that VAR2CSA is compactly organized into a globular structure containing C4S-binding channel, and that DBL5ε-DBL6ε arm is attached to the NTS-ID3 core structure. However, the structural elements involved in inter-domain interactions that stabilize the VAR2CSA structure remain largely not understood. Here, limited proteolysis and peptide mapping by mass spectrometry showed that VAR2CSA contains several inter-domain disulfide bonds that stabilize its compact structure. Chemical crosslinking-mass spectrometry showed that all IDs interact with DBL4ε; additionally, IDs interact with other DBL domains, demonstrating that IDs are the key structural scaffolds that shape the functional NTS-ID3 core. Ligand binding analysis suggested that NTS considerably restricts the C4S binding. Overall, our study revealed that inter-domain disulfide bonds and interactions between IDs and DBL domains contribute to the stability of VAR2CSA structural architecture and formation of C4S-binding channel.
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23
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Hu X, Zhao J, Zhao J, Yang E, Jia M. Genome-wide liver transcriptomic profiling of a malaria mouse model reveals disturbed immune and metabolic responses. Parasit Vectors 2023; 16:40. [PMID: 36717945 PMCID: PMC9885691 DOI: 10.1186/s13071-023-05672-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The liver is responsible for a range of functions in vertebrates, such as metabolism and immunity. In malaria, the liver plays a crucial role in the interaction between the parasite and host. Although malarial hepatitis is a common clinical complication of severe malaria, other malaria-related liver changes have been overlooked during the blood stage of the parasite life-cycle, in contrast to the many studies that have focused on parasite invasion of and replication in the liver during the hepatic stage of the parasite. METHODS A rodent model of malaria was established using Plasmodium yoelii strain 17XL, a lethal strain of rodent malaria, for liver transcriptomic profiling. RESULTS Differentially expressed messenger RNAs were associated with innate and adaptive immune responses, while differentially expressed long noncoding RNAs were enriched in the regulation of metabolism-related pathways, such as lipid metabolism. The coexpression network showed that host genes were related to cellular transport and tissue remodeling. Hub gene analysis of P. yoelii indicated that ubiquitination genes that were coexpressed with the host were evolutionarily conserved. CONCLUSIONS Our analysis yielded evidence of activated immune responses, aberrant metabolic processes and tissue remodeling changes in the livers of mice with malaria during the blood stage of the parasite, which provided a systematic outline of liver responses during Plasmodium infection.
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Affiliation(s)
- Xueyan Hu
- grid.11135.370000 0001 2256 9319Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China
| | - Jie Zhao
- grid.11135.370000 0001 2256 9319Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China
| | - Junhui Zhao
- grid.11135.370000 0001 2256 9319Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China
| | - Ence Yang
- grid.11135.370000 0001 2256 9319Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China ,grid.11135.370000 0001 2256 9319Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China
| | - Mozhi Jia
- grid.11135.370000 0001 2256 9319Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China
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24
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Alves FDM, Bellei JCB, Barbosa CDS, Duarte CL, da Fonseca AL, Pinto ACDS, Raimundo FO, Carpinter BA, Lemos ASDO, Coimbra ES, Taranto AG, Rocha VN, de Pilla Varotti F, Ribeiro Viana GH, Scopel KKG. Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria. Pathogens 2022; 11:pathogens11121529. [PMID: 36558863 PMCID: PMC9781199 DOI: 10.3390/pathogens11121529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/08/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022] Open
Abstract
Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria (CM) and is responsible for deaths and significant neurocognitive sequelae throughout life. In this context and considering the emergence and spread of drug-resistant P. falciparum isolates, the search for new antimalarial candidates becomes urgent. β-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds has been reported. Herein, we designed 20 chemical entities and performed an in silico virtual screening against a pool of P. falciparum molecular targets, the Brazilian Malaria Molecular Targets (BRAMMT). Seven structures showed potential to interact with PfFNR, PfPK7, PfGrx1, and PfATP6, being synthesized and evaluated for in vitro antiplasmodial activity. Among them, compounds 3−6 and 10 inhibited the growth of the W2 strain at µM concentrations, with low cytotoxicity against the human cell line. In silico physicochemical and pharmacokinetic properties were found to be favorable for oral administration. The compound 10 provided the best results against CM, with important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and suppressive (82%) assays. Furthermore, this compound was able to elongate mice survival and protect them against the development of the experimental model of CM (>65%). Compound 10 also induced reduction of the NO level, possibly by interaction with iNOS. Therefore, this alkaloid showed promising activity for the treatment of malaria and was able to prevent the development of experimental cerebral malaria (ECM), probably by reducing NO synthesis.
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Affiliation(s)
- Fernanda de Moura Alves
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Jessica Correa Bezerra Bellei
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Camila de Souza Barbosa
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Caíque Lopes Duarte
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Amanda Luisa da Fonseca
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Ana Claudia de Souza Pinto
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Felipe Oliveira Raimundo
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Bárbara Albuquerque Carpinter
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Ari Sérgio de Oliveira Lemos
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Elaine Soares Coimbra
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Alex Gutterres Taranto
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
| | - Vinícius Novaes Rocha
- Research Center of Pathology and Veterinary Histology, Departament of Veterinary Medicine, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
| | - Fernando de Pilla Varotti
- Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
- Correspondence: (F.d.P.V.); (K.K.G.S.)
| | | | - Kézia K. G. Scopel
- Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
- Correspondence: (F.d.P.V.); (K.K.G.S.)
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25
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Chaves JB, Portugal Tavares de Moraes B, Regina Ferrarini S, Noé da Fonseca F, Silva AR, Gonçalves-de-Albuquerque CF. Potential of nanoformulations in malaria treatment. Front Pharmacol 2022; 13:999300. [PMID: 36386185 PMCID: PMC9645116 DOI: 10.3389/fphar.2022.999300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 10/03/2022] [Indexed: 11/29/2022] Open
Abstract
Malaria is caused by the protozoan Plasmodium sp and affects millions of people worldwide. Its clinical form ranges from asymptomatic to potentially fatal and severe. Current treatments include single drugs such as chloroquine, lumefantrine, primaquine, or in combination with artemisinin or its derivatives. Resistance to antimalarial drugs has increased; therefore, there is an urgent need to diversify therapeutic approaches. The disease cycle is influenced by biological, social, and anthropological factors. This longevity and complexity contributes to the records of drug resistance, where further studies and proposals for new therapeutic formulations are needed for successful treatment of malaria. Nanotechnology is promising for drug development. Preclinical formulations with antimalarial agents have shown positive results, but only a few have progressed to clinical phase. Therefore, studies focusing on the development and evaluation of antimalarial formulations should be encouraged because of their enormous therapeutic potential.
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Affiliation(s)
- Janaina Braga Chaves
- Immunopharmacology Laboratory, Department of Biochemistry, Federal University of the State of Rio de Janeiro—UNIRIO, Rio de Janeiro, Brazil
| | - Bianca Portugal Tavares de Moraes
- Immunopharmacology Laboratory, Department of Biochemistry, Federal University of the State of Rio de Janeiro—UNIRIO, Rio de Janeiro, Brazil
| | - Stela Regina Ferrarini
- Pharmaceutical Nanotechnology Laboratory, Federal University of Mato Grosso of Sinop Campus—UFMT, Cuiabá, Brazil
| | - Francisco Noé da Fonseca
- Empresa Brasileira de Pesquisa Agropecuária, Parque Estação Biológica—PqEB, EMBRAPA, Brasília, Brazil
| | - Adriana Ribeiro Silva
- Immunopharmacology Laboratory, Oswaldo Cruz Foundation, FIOCRUZ—UNIRIO, Rio de Janeiro, Brazil
| | - Cassiano Felippe Gonçalves-de-Albuquerque
- Immunopharmacology Laboratory, Department of Biochemistry, Federal University of the State of Rio de Janeiro—UNIRIO, Rio de Janeiro, Brazil
- Immunopharmacology Laboratory, Oswaldo Cruz Foundation, FIOCRUZ—UNIRIO, Rio de Janeiro, Brazil
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Mohamed Y, El-Maradny YA, Saleh AK, Nayl AA, El-Gendi H, El-Fakharany EM. A comprehensive insight into current control of COVID-19: Immunogenicity, vaccination, and treatment. Biomed Pharmacother 2022; 153:113499. [PMID: 36076589 PMCID: PMC9343749 DOI: 10.1016/j.biopha.2022.113499] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/29/2022] [Accepted: 07/30/2022] [Indexed: 02/07/2023] Open
Abstract
The healthy immune system eliminates pathogens and maintains tissue homeostasis through extraordinarily complex networks with feedback systems while avoiding potentially massive tissue destruction. Many parameters influence humoral and cellular vaccine responses, including intrinsic and extrinsic, environmental, and behavioral, nutritional, perinatal and administrative parameters. The relative contributions of persisting antibodies and immune memory as well as the determinants of immune memory induction, to protect against specific diseases are the main parameters of long-term vaccine efficacy. Natural and vaccine-induced immunity and monoclonal antibody immunotherapeutic, may be evaded by SARS-CoV-2 variants. Besides the complications of the production of COVID-19 vaccinations, there is no effective single treatment against COVID-19. However, administration of a combined treatment at different stages of COVID-19 infection may offer some cure assistance. Combination treatment of antiviral drugs and immunomodulatory drugs may reduce inflammation in critical COVID-19 patients with cytokine release syndrome. Molnupiravir, remdesivir and paxlovid are the approved antiviral agents that may reduce the recovery time. In addition, immunomodulatory drugs such as lactoferrin and monoclonal antibodies are used to control inflammatory responses in their respective auto-immune conditions. Therefore, the widespread occurrence of highly transmissible variants like Delta and Omicron indicates that there is still a lot of work to be done in designing efficient vaccines and medicines for COVID-19. In this review, we briefly discussed the immunological response against SARS-CoV-2 and the vaccines approved by the World Health Organization (WHO) for COVID-19, their mechanisms, and side effects. Moreover, we mentioned various treatment trials and strategies for COVID-19.
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Affiliation(s)
- Yasser Mohamed
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg EL-Arab, Alexandria 21934, Egypt; Laboratory of Kafr El-Sheikh Fever Hospital, Kafr El-Sheikh Fever Hospital, 33511 Kafr El-Sheikh, Egypt.
| | - Yousra A El-Maradny
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg EL-Arab, Alexandria 21934, Egypt; Microbiology Department, High Institute of Public Health, Alexandria University, Alexandria 21526, Egypt.
| | - Ahmed K Saleh
- Cellulose and Paper Department, National Research Centre, El-Tahrir St., Dokki, P.O. 12622, Giza, Egypt
| | - AbdElAziz A Nayl
- Department of Chemistry, College of Science, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia.
| | - Hamada El-Gendi
- Bioprocess Development Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Universities and Research Institutes zone, New Borg El-Arab, Alexandria 21934, Egypt.
| | - Esmail M El-Fakharany
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg EL-Arab, Alexandria 21934, Egypt.
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Pohl K, Cockburn IA. Innate immunity to malaria: The good, the bad and the unknown. Front Immunol 2022; 13:914598. [PMID: 36059493 PMCID: PMC9437427 DOI: 10.3389/fimmu.2022.914598] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/21/2022] [Indexed: 12/04/2022] Open
Abstract
Malaria is the cause of 600.000 deaths annually. However, these deaths represent only a tiny fraction of total malaria cases. Repeated natural infections with the causative agent, Plasmodium sp. parasites, induce protection from severe disease but not sterile immunity. Thus, immunity to Plasmodium is incomplete. Conversely, immunization with attenuated sporozoite stage parasites can induce sterile immunity albeit after multiple vaccinations. These different outcomes are likely to be influenced strongly by the innate immune response to different stages of the parasite lifecycle. Even small numbers of sporozoites can induce a robust proinflammatory type I interferon response, which is believed to be driven by the sensing of parasite RNA. Moreover, induction of innate like gamma-delta cells contributes to the development of adaptive immune responses. Conversely, while blood stage parasites can induce a strong proinflammatory response, regulatory mechanisms are also triggered. In agreement with this, intact parasites are relatively weakly sensed by innate immune cells, but isolated parasite molecules, notably DNA and RNA can induce strong responses. Thus, the innate response to Plasmodium parasite likely represents a trade-off between strong pro-inflammatory responses that may potentiate immunity and regulatory processes that protect the host from cytokine storms that can induce life threatening illness.
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Affiliation(s)
- Kai Pohl
- Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität Berlin, Berlin, Germany
- Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University Canberra, Canberra, ACT, Australia
| | - Ian A. Cockburn
- Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University Canberra, Canberra, ACT, Australia
- *Correspondence: Ian A. Cockburn,
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Peterson MS, Joyner CJ, Lapp SA, Brady JA, Wood JS, Cabrera-Mora M, Saney CL, Fonseca LL, Cheng WT, Jiang J, Soderberg SR, Nural MV, Hankus A, Machiah D, Karpuzoglu E, DeBarry JD, Tirouvanziam R, Kissinger JC, Moreno A, Gumber S, Voit EO, Gutierrez JB, Cordy RJ, Galinski MR. Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins. Front Cell Infect Microbiol 2022; 12:888496. [PMID: 35811680 PMCID: PMC9260704 DOI: 10.3389/fcimb.2022.888496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.
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Affiliation(s)
- Mariko S. Peterson
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Chester J. Joyner
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
| | - Stacey A. Lapp
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Jessica A. Brady
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA, United States
| | - Jennifer S. Wood
- Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States
| | - Monica Cabrera-Mora
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Celia L. Saney
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Luis L. Fonseca
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
| | - Wayne T. Cheng
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
| | - Jianlin Jiang
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Stephanie R. Soderberg
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Mustafa V. Nural
- Institute of Bioinformatics, University of Georgia, Athens, GA, United States
| | - Allison Hankus
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Deepa Machiah
- Division of Pathology, Yerkes National Primate Research Center, Atlanta, GA, United States
| | - Ebru Karpuzoglu
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Jeremy D. DeBarry
- Institute of Bioinformatics, University of Georgia, Athens, GA, United States
| | - Rabindra Tirouvanziam
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Jessica C. Kissinger
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Institute of Bioinformatics, University of Georgia, Athens, GA, United States
- Department of Genetics, University of Georgia, Athens, GA, United States
| | - Alberto Moreno
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Sanjeev Gumber
- Division of Pathology, Yerkes National Primate Research Center, Atlanta, GA, United States
- Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, GA, United States
| | - Eberhard O. Voit
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
| | - Juan B. Gutierrez
- Department of Mathematics, University of Georgia, Athens, GA, United States
| | - Regina Joice Cordy
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
| | - Mary R. Galinski
- Emory National Primate Research Center, Emory University, Atlanta, GA, United States
- Emory Vaccine Center, Emory University, Atlanta, GA, United States
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
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Zoia M, Yesodha Subramanian B, Eriksson KK, Ravi MS, Yaghmaei S, Fellay I, Scolari B, Walch M, Mantel PY. Validation of Effective Extracellular Vesicles Isolation Methods Adapted to Field Studies in Malaria Endemic Regions. Front Cell Dev Biol 2022; 10:812244. [PMID: 35652104 PMCID: PMC9149222 DOI: 10.3389/fcell.2022.812244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 04/13/2022] [Indexed: 11/13/2022] Open
Abstract
Malaria affects the poorer regions of the world and is of tremendous health and economic burden for developing countries. Extracellular vesicles (EVs) are small vesicles released by almost any cells in the human body, including malaria infected red blood cells. Recent evidence shows that EVs might contribute to the pathogenesis of malaria. In addition, EVs hold considerable value in biomarker discovery. However, there are still significant gaps in our understanding of EV biology. So far most of our knowledge about EVs in malaria comes from in vitro work. More field studies are required to gain insight into their contribution to the disease and pathogenesis under physiological conditions. However, to perform research on EVs in low-income regions might be challenging due to the lack of appropriate equipment to isolate EVs. Therefore, there is a need to develop and validate EV extraction protocols applicable to poorly equipped laboratories. We established and validated two protocols for EV isolation from cell culture supernatants, rodent and human plasma. We compared polyethylene glycol (PEG) and salting out (SA) with sodium acetate for precipitation of EVs. We then characterized the EVs by Transmission Electron Microscopy (TEM), Western Blot, Size-exclusion chromatography (SEC), bead-based flow cytometry and protein quantification. Both protocols resulted in efficient purification of EVs without the need of expensive material or ultracentrifugation. Furthermore, the procedure is easily scalable to work with large and small sample volumes. Here, we propose that both of our approaches can be used in resource limited countries, therefore further helping to close the gap in knowledge of EVs during malaria.
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Affiliation(s)
- Matteo Zoia
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Bibin Yesodha Subramanian
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Klara Kristin Eriksson
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Meera Sruthi Ravi
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Shekoofeh Yaghmaei
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Isabelle Fellay
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Brigitte Scolari
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Michael Walch
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Pierre-Yves Mantel
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
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30
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Ahmed W, Karabaliev M, Gao C. Taking chiral polymers toward immune regulation. JOURNAL OF POLYMER SCIENCE 2022. [DOI: 10.1002/pol.20210936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Wajiha Ahmed
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering Zhejiang University Hangzhou China
| | - Miroslav Karabaliev
- Department of Medical Physics, Biophysics and Radiology, Faculty of Medicine Trakia University Bulgaria
| | - Changyou Gao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering Zhejiang University Hangzhou China
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31
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Tornyigah B, Blankson SO, Adamou R, Moussiliou A, Rietmeyer L, Tettey P, Dikroh L, Addo B, Lamptey H, Alao MJ, Amoussou A, Padounou C, Roussilhon C, Pons S, Mensah BA, Ndam NT, Tahar R. Specific Combinations of Inflammatory, Angiogenesis and Vascular Integrity Biomarkers Are Associated with Clinical Severity, Coma and Mortality in Beninese Children with Plasmodium Falciparum Malaria. Diagnostics (Basel) 2022; 12:diagnostics12020524. [PMID: 35204613 PMCID: PMC8871337 DOI: 10.3390/diagnostics12020524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/07/2022] [Accepted: 02/15/2022] [Indexed: 12/16/2022] Open
Abstract
Malaria-related deaths could be prevented if powerful diagnostic and reliable prognostic biomarkers were available to allow rapid prediction of the clinical severity allowing adequate treatment. Using quantitative ELISA, we assessed the plasma concentrations of Procalcitonin, Pentraxine-3, Ang-2, sTie-2, suPAR, sEPCR and sICAM-1 in a cohort of Beninese children with malaria to investigate their potential association with clinical manifestations of malaria. We found that all molecules showed higher levels in children with severe or cerebral malaria compared to those with uncomplicated malaria (p-value < 0.005). Plasma concentrations of Pentraxine-3, Procalcitonin, Ang-2 and the soluble receptors were significantly higher in children with coma as defined by a Blantyre Coma Score < 3 (p < 0.001 for Pentraxine-3, suPAR, and sTie-2, p = 0.004 for PCT, p = 0.005 for sICAM-1, p = 0.04 for Ang-2). Moreover, except for the PCT level, the concentrations of Pentraxine-3, suPAR, sEPCR, sICAM-1, sTie-2 and Ang-2 were higher among children who died from severe malaria compared to those who survived (p = 0.037, p = 0.035, p < 0.0001, p= 0.0008, p = 0.01 and p = 0.02, respectively). These findings indicate the ability of these molecules to accurately discriminate among clinical manifestations of malaria, thus, they might be potentially useful for the early prognostic of severe and fatal malaria, and to improve management of severe cases.
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Affiliation(s)
- Bernard Tornyigah
- Université de Paris, MERIT, IRD, 75006 Paris, France; (B.T.); (S.O.B.); (L.R.); (N.T.N.)
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Samuel Odarkwei Blankson
- Université de Paris, MERIT, IRD, 75006 Paris, France; (B.T.); (S.O.B.); (L.R.); (N.T.N.)
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Rafiou Adamou
- Institut de Recherche Clinique du Benin (IRCB), Calavi, Benin; (R.A.); (A.M.)
| | - Azizath Moussiliou
- Institut de Recherche Clinique du Benin (IRCB), Calavi, Benin; (R.A.); (A.M.)
| | - Lauriane Rietmeyer
- Université de Paris, MERIT, IRD, 75006 Paris, France; (B.T.); (S.O.B.); (L.R.); (N.T.N.)
| | - Patrick Tettey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Liliane Dikroh
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Bernard Addo
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Helena Lamptey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Maroufou J. Alao
- Département de Pédiatrie, Hôpital Mère-Enfant la Lagune (CHUMEL), Cotonou, Benin;
| | - Annick Amoussou
- Service de Pédiatrie, Centre Hospitalo-Universitaire, Suruléré (CHU-Suruléré), Cotonou, Benin;
| | - Caroline Padounou
- Centre Hospitalier Universitaire de l’Oueme/Plateau, Porto-Novo, Benin;
| | - Christian Roussilhon
- Unité de Génétique Fonctionnelle des Maladies Infectieuses, Département Génomes et Génétique, Institut Pasteur, 28 Rue du Docteur Roux, 75015 Paris, France;
| | - Sylvie Pons
- Laboratoire Commun de Recherche Hospices Civils de Lyon-BioMérieux, Centre Hospitalier Lyon-Sud, Bâtiment 3F, 165 chemin du Grand Revoyet, 69310 Pierre-Bénite, France;
| | - Benedicta Ayiedu Mensah
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Nicaise Tuikue Ndam
- Université de Paris, MERIT, IRD, 75006 Paris, France; (B.T.); (S.O.B.); (L.R.); (N.T.N.)
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
| | - Rachida Tahar
- Université de Paris, MERIT, IRD, 75006 Paris, France; (B.T.); (S.O.B.); (L.R.); (N.T.N.)
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana; (P.T.); (L.D.); (B.A.); (H.L.); (B.A.M.)
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana
- Correspondence: ; Tel.: +33-153-739-933
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Lee MS, Inoue T, Ise W, Matsuo-Dapaah J, Wing JB, Temizoz B, Kobiyama K, Hayashi T, Patil A, Sakaguchi S, Simon AK, Bezbradica JS, Nagatoishi S, Tsumoto K, Inoue JI, Akira S, Kurosaki T, Ishii KJ, Coban C. B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice. J Exp Med 2022; 219:e20211336. [PMID: 34910106 PMCID: PMC8679780 DOI: 10.1084/jem.20211336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 01/30/2023] Open
Abstract
The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell-intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell-specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.
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Affiliation(s)
- Michelle S.J. Lee
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takeshi Inoue
- Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Wataru Ise
- Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Julia Matsuo-Dapaah
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - James B. Wing
- Laboratory of Human Immunology (Single Cell Immunology), Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Human Single Cell Immunology Team, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Burcu Temizoz
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kouji Kobiyama
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomoya Hayashi
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | | | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - A. Katharina Simon
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Jelena S. Bezbradica
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Satoru Nagatoishi
- Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kouhei Tsumoto
- Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Jun-Ichiro Inoue
- Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shizuo Akira
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Tomohiro Kurosaki
- Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Ken J. Ishii
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Wei W, Cheng W, Dai W, Lu F, Cheng Y, Jiang T, Ren Z, Xie Y, Xu J, Zhao Q, Yu X, Yin Y, Li J, Dong H. A Nanodrug Coated with Membrane from Brain Microvascular Endothelial Cells Protects against Experimental Cerebral Malaria. NANO LETTERS 2022; 22:211-219. [PMID: 34967631 DOI: 10.1021/acs.nanolett.1c03514] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Human malaria is a global life-threatening infectious disease. Cerebral malaria (CM) induced by Plasmodium falciparum parasites accounts for 90% of malaria deaths. Treating CM is challenging due to inadequate treatment options and the development of drug resistance. We describe a nanoparticle formulation of the antimalarial drug dihydroartemisinin that is coated in a biomimetic membrane derived from brain microvascular endothelial cells (BMECs) and test its therapeutic efficacy in a mouse model of experimental cerebral malaria (ECM). The membrane-coated nanoparticle drug has a prolonged drug-release profile and enhanced dual targeting killing efficacy toward parasites residing in red blood cells (iRBCs) and iRBCs obstructed in the BMECs (for both rodent and human). In a mice ECM model, the nanodrug protects the brain, liver, and spleen from infection-induced damage and improves the survival rate of mice. This so-called nanodrug offers new insight into engineering nanoparticle-based therapeutics for malaria and other parasitic pathogen infections.
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Affiliation(s)
- Wei Wei
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Weijia Cheng
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Wenhao Dai
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Feng Lu
- School of Medicine, Yangzhou University, Yangzhou 225009, China
| | - Yaru Cheng
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Tingting Jiang
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Zhenyu Ren
- School of Medicine, Yangzhou University, Yangzhou 225009, China
| | - Yiting Xie
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Jiahui Xu
- School of Medicine, Yangzhou University, Yangzhou 225009, China
| | - Qun Zhao
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Xianjun Yu
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Yi Yin
- School of Medicine, Yangzhou University, Yangzhou 225009, China
| | - Jian Li
- Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Haifeng Dong
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing 100083, China
- Marshall Laboratory of Biomedical Engineering, Research Center for Biosensor and Nanotheranostic, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China
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Carvalho Cabral P, Tekade K, Stegeman SK, Olivier M, Cermakian N. The involvement of host circadian clocks in the regulation of the immune response to parasitic infections in mammals. Parasite Immunol 2021; 44:e12903. [PMID: 34964129 DOI: 10.1111/pim.12903] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 11/29/2022]
Abstract
Circadian rhythms are recurring variations of physiology with a period of ~24 hours, generated by circadian clocks located throughout the body. Studies have shown a circadian regulation of many aspects of immunity. Immune cells have intrinsic clock mechanisms, and innate and adaptive immune responses - such as leukocyte migration, magnitude of inflammation, cytokine production and cell differentiation - are under circadian control. This circadian regulation has consequences for infections including parasitic infections. In the context of Leishmania infection, the circadian clock within host immune cells modulates the magnitude of the infection and the inflammatory response triggered by the parasite. As for malaria, rhythms within the immune system were shown to impact the developmental cycles of Plasmodium parasites within red blood cells. Further, host circadian rhythms impact infections by multicellular parasites; for example, infection with helminth Trichuris muris shows different kinetics of worm expulsion depending on time of day of infection, a variation that depends on the dendritic cell clock. Although the research on the circadian control of immunity in the context of parasitic infections is in its infancy, the research reviewed here suggests a crucial involvement of host circadian rhythms in immunity on the development and progression of parasitic infections.
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Affiliation(s)
| | - Kimaya Tekade
- Douglas Research Centre, McGill University, Montreal, QC, H4H 1R3, Canada
| | - Sophia K Stegeman
- Douglas Research Centre, McGill University, Montreal, QC, H4H 1R3, Canada
| | - Martin Olivier
- Research Institute of the McGill University Health Center, McGill University, Montreal, QC, H4A 3J1, Canada
| | - Nicolas Cermakian
- Douglas Research Centre, McGill University, Montreal, QC, H4H 1R3, Canada
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Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria. Molecules 2021; 26:molecules26247521. [PMID: 34946603 PMCID: PMC8707619 DOI: 10.3390/molecules26247521] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/18/2021] [Accepted: 08/24/2021] [Indexed: 01/12/2023] Open
Abstract
Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.
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36
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Donnelly E, de Water JV, Luckhart S. Malaria-induced bacteremia as a consequence of multiple parasite survival strategies. CURRENT RESEARCH IN MICROBIAL SCIENCES 2021; 2:100036. [PMID: 34841327 PMCID: PMC8610325 DOI: 10.1016/j.crmicr.2021.100036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/30/2022] Open
Abstract
Globally, malaria continues to be an enormous public health burden, with concomitant parasite-induced damage to the gastrointestinal (GI) barrier resulting in bacteremia-associated morbidity and mortality in both adults and children. Infected red blood cells sequester in and can occlude the GI microvasculature, ultimately leading to disruption of the tight and adherens junctions that would normally serve as a physical barrier to translocating enteric bacteria. Mast cell (MC) activation and translocation to the GI during malaria intensifies damage to the physical barrier and weakens the immunological barrier through the release of enzymes and factors that alter the host response to escaped enteric bacteria. In this context, activated MCs release Th2 cytokines, promoting a balanced Th1/Th2 response that increases local and systemic allergic inflammation while protecting the host from overwhelming Th1-mediated immunopathology. Beyond the mammalian host, recent studies in both the lab and field have revealed an association between a Th2-skewed host response and success of parasite transmission to mosquitoes, biology that is evocative of parasite manipulation of the mammalian host. Collectively, these observations suggest that malaria-induced bacteremia may be, in part, an unintended consequence of a Th2-shifted host response that promotes parasite survival and transmission. Future directions of this work include defining the factors and mechanisms that precede the development of bacteremia, which will enable the development of biomarkers to simplify diagnostics, the identification of therapeutic targets to improve patient outcomes and better understanding of the consequences of clinical interventions to transmission blocking strategies.
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Affiliation(s)
- Erinn Donnelly
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Judy Van de Water
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA
| | - Shirley Luckhart
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID, USA
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37
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Matsuo-Dapaah J, Lee MSJ, Ishii KJ, Tainaka K, Coban C. Using a new three-dimensional CUBIC tissue-clearing method to examine the brain during experimental cerebral malaria. Int Immunol 2021; 33:587-594. [PMID: 34455438 DOI: 10.1093/intimm/dxab060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/28/2021] [Indexed: 11/13/2022] Open
Abstract
Cerebral malaria (CM) is a life-threatening complication of the malaria disease caused by Plasmodium falciparum infection and is responsible for the death of half a million people annually. The molecular pathogenesis underlying CM in humans is not completely understood, although sequestration of infected erythrocytes in cerebral microvessels is thought to play a major role. In contrast, experimental cerebral malaria (ECM) models in mice have been thought to be distinct from human CM, and are mainly caused by inflammatory mediators. Here, to understand the spatial distribution and the potential sequestration of parasites in the whole-brain microvessels during a mouse model of ECM, we utilized the new tissue-clearing method CUBIC (Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational analysis) with light-sheet fluorescent microscopy (LSFM), and reconstructed images in three dimensions (3D). We demonstrated significantly greater accumulation of Plasmodium berghei ANKA (PbANKA) parasites in the olfactory bulb (OB) of mice, compared with the other parts of the brain, including the cerebral cortex, cerebellum and brainstem. Furthermore, we show that PbANKA parasites preferentially accumulate in the brainstem when the OB is surgically removed. This study therefore not only highlights a successful application of CUBIC tissue-clearing technology to visualize the whole brain and its microvessels during ECM, but it also shows CUBIC's future potential for visualizing pathological events in the whole ECM brain at the cellular level, an achievement that would greatly advance our understanding of human cerebral malaria.
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Affiliation(s)
- Julia Matsuo-Dapaah
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan.,Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Michelle Sue Jann Lee
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan
| | - Ken J Ishii
- Graduate School of Medicine, University of Tokyo, Tokyo, Japan.,Division of Vaccine Science, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan.,International Vaccine Design Center, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan.,Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Kazuki Tainaka
- Department of System Pathology for Neurological Disorders, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.,Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Osaka, Japan
| | - Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan.,Graduate School of Medicine, University of Tokyo, Tokyo, Japan.,International Vaccine Design Center, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo, Japan.,Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
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38
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Immunoprofiles associated with controlled human malaria infection and naturally acquired immunity identify a shared IgA pre-erythrocytic immunoproteome. NPJ Vaccines 2021; 6:115. [PMID: 34518543 PMCID: PMC8438027 DOI: 10.1038/s41541-021-00363-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Knowledge of the Plasmodium falciparum antigens that comprise the human liver stage immunoproteome is important for pre-erythrocytic vaccine development, but, compared with the erythrocytic stage immunoproteome, more challenging to classify. Previous studies of P. falciparum antibody responses report IgG and rarely IgA responses. We assessed IgG and IgA antibody responses in adult sera collected during two controlled human malaria infection (CHMI) studies in malaria-naïve volunteers and in 1- to 6-year-old malaria-exposed Malian children on a 251 P. falciparum antigen protein microarray. IgG profiles in the two CHMI groups were equivalent and differed from Malian children. IgA profiles were robust in the CHMI groups and a subset of Malian children. We describe immunoproteome differences in naïve vs. exposed individuals and report pre-erythrocytic proteins recognized by the immune system. IgA responses detected in this study expand the list of pre-erythrocytic antigens for further characterization as potential vaccine candidates.
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39
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Galán-Salinas A, Corral-Ruíz G, Pérez-Vega MJ, Fabila-Castillo L, Silva-García R, Marquina-Castillo B, León-Contreras JC, Barrios-Payán J, Francisco-Cruz A, Montecillo-Aguado M, Huerta-Yepez S, Calderón-Amador J, Flores-Romo L, Hernández-Pando R, Sánchez-Torres LE. Monocyte Locomotion Inhibitory Factor confers neuroprotection and prevents the development of murine cerebral malaria. Int Immunopharmacol 2021; 97:107674. [PMID: 34044183 DOI: 10.1016/j.intimp.2021.107674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/30/2021] [Accepted: 04/10/2021] [Indexed: 10/21/2022]
Abstract
Cerebral malaria (CM) is a neurological complication derived from the Plasmodium falciparum infection in humans. The mechanisms involved in the disease progression are still not fully understood, but both the sequestration of infected red blood cells (iRBC) and leukocytes and an exacerbated host inflammatory immune response are significant factors. In this study, we investigated the effect of Monocyte Locomotion Inhibitory Factor (MLIF), an anti-inflammatory peptide, in a well-characterized murine model of CM. Our data showed that the administration of MLIF increased the survival and avoided the neurological signs of CM in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. MLIF administration down-regulated systemic inflammatory mediators such as IFN-γ, TNF-α, IL-6, CXCL2, and CCL2, as well as the in situ expression of TNF-α in the brain. In the same way, MLIF reduced the expression of CD31, CD36, CD54, and CD106 in the cerebral endothelium of infected animals and prevented the sequestration of iRBC and leucocytes in the brain microvasculature. Furthermore, MLIF inhibited the activation of astrocytes and microglia and preserved the integrity of the blood-brain barrier (BBB). In conclusion, our results demonstrated that the administration of MLIF increased survival and conferred neuroprotection by decreasing neuroinflammation in murine CM.
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Affiliation(s)
- A Galán-Salinas
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico; Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico
| | - G Corral-Ruíz
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico; Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico
| | - M J Pérez-Vega
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico; Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico
| | - L Fabila-Castillo
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico; Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico
| | - R Silva-García
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, CMN-Siglo XXI, IMSS, México City, Mexico
| | - B Marquina-Castillo
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico
| | - J C León-Contreras
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico
| | - J Barrios-Payán
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico
| | - A Francisco-Cruz
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - M Montecillo-Aguado
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, México City, Mexico
| | - S Huerta-Yepez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, México City, Mexico
| | - J Calderón-Amador
- Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico; Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Instituto Politécnico Nacional, México City, Mexico
| | - L Flores-Romo
- Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Instituto Politécnico Nacional, México City, Mexico
| | - R Hernández-Pando
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico.
| | - L E Sánchez-Torres
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico.
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40
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Katsoulis O, Georgiadou A, Cunnington AJ. Immunopathology of Acute Kidney Injury in Severe Malaria. Front Immunol 2021; 12:651739. [PMID: 33968051 PMCID: PMC8102819 DOI: 10.3389/fimmu.2021.651739] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/06/2021] [Indexed: 11/13/2022] Open
Abstract
Acute kidney injury (AKI) is a common feature of severe malaria, and an independent risk factor for death. Previous research has suggested that an overactivation of the host inflammatory response is at least partly involved in mediating the kidney damage observed in P. falciparum patients with AKI, however the exact pathophysiology of AKI in severe malaria remains unknown. The purpose of this mini-review is to describe how different aspects of malaria pathology, including parasite sequestration, microvascular obstruction and extensive intravascular hemolysis, may interact with each other and contribute to the development of AKI in severe malaria, by amplifying the damaging effects of the host inflammatory response. Here, we highlight the importance of considering how the systemic effects and multi-organ involvement of malaria are intertwined with the localized effects on the kidney.
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Affiliation(s)
- Orestis Katsoulis
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United Kingdom
| | - Athina Georgiadou
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United Kingdom
- Centre for Paediatrics and Child Health, Imperial College London, London, United Kingdom
| | - Aubrey J. Cunnington
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United Kingdom
- Centre for Paediatrics and Child Health, Imperial College London, London, United Kingdom
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41
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Tian R, Xu J, Luo Q, Hou C, Liu J. Rational Design and Biological Application of Antioxidant Nanozymes. Front Chem 2021; 8:831. [PMID: 33644000 PMCID: PMC7905316 DOI: 10.3389/fchem.2020.00831] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022] Open
Abstract
Nanozyme is a type of nanostructured material with intrinsic enzyme mimicking activity, which has been increasingly studied in the biological field. Compared with natural enzymes, nanozymes have many advantages, such as higher stability, higher design flexibility, and more economical production costs. Nanozymes can be used to mimic natural antioxidant enzymes to treat diseases caused by oxidative stress through reasonable design and modification. Oxidative stress is caused by imbalances in the production and elimination of reactive oxygen species (ROS) and reactive nitrogen species (RNS). This continuous oxidative stress can cause damage to some biomolecules and significant destruction to cell structure and function, leading to many physiological diseases. In this paper, the methods to improve the antioxidant properties of nanozymes were reviewed, and the applications of nanozyme antioxidant in the fields of anti-aging, cell protection, anti-inflammation, wound repair, cancer, traumatic brain injury, and nervous system diseases were introduced. Finally, the future challenges and prospects of nanozyme as an ideal antioxidant were discussed.
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Affiliation(s)
- Ruizhen Tian
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
| | - Jiayun Xu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China.,College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, China
| | - Quan Luo
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
| | - Chunxi Hou
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
| | - Junqiu Liu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
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42
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Osei SA, Biney RP, Obese E, Agbenyeku MAP, Attah IY, Ameyaw EO, Boampong JN. Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice. Malar J 2021; 20:113. [PMID: 33632233 PMCID: PMC7908739 DOI: 10.1186/s12936-021-03658-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 02/19/2021] [Indexed: 12/01/2022] Open
Abstract
Background Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. Methods Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg−1), artesunate (ART: 1, 2, 4, 8, 16 mg kg−1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg−1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded. Results ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg−1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. Conclusion Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.
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Affiliation(s)
- Silas Acheampong Osei
- Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.,School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Robert Peter Biney
- School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana.,Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Ernest Obese
- School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana.,Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Mary Atta-Panyi Agbenyeku
- Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Isaac Yaw Attah
- Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.,School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Elvis Ofori Ameyaw
- Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana. .,School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Johnson Nyarko Boampong
- Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.,School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
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43
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Sey ICM, Ehimiyein AM, Bottomley C, Riley EM, Mooney JP. Does Malaria Cause Diarrhoea? A Systematic Review. Front Med (Lausanne) 2020; 7:589379. [PMID: 33330549 PMCID: PMC7717985 DOI: 10.3389/fmed.2020.589379] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/22/2020] [Indexed: 11/13/2022] Open
Abstract
Malaria is a systemic febrile disease that may progress to prostration, respiratory distress, encephalopathy, anemia, and death. Malaria is also an established risk factor for invasive bacterial disease caused, in the majority of cases, by invasive enteropathogens and in particular by non-Typhoidal Salmonella (NTS). Whilst various malaria-related pathologies have been implicated in the risk of NTS bacteraemia in animal models, including intestinal dysbiosis and loss of gut homeostasis, clinical evidence is lacking. As a first step in gathering such evidence, we conducted a systematic review of clinical and epidemiological studies reporting the prevalence of diarrhoea among malaria cases and vice versa. Database searches for "plasmodium" and "diarrhoea" identified 1,771 articles; a search for "plasmodium" and "gastroenteritis" identified a further 215 articles. After review, 66 articles specified an association between the search terms and referred primarily, but not exclusively, to Plasmodium falciparum infections. Overall, between 1.6 and 44% of patients with acute malaria infection reported symptoms of diarrhoea (812 of 7,267 individuals, 11%) whereas 5-42% of patients presenting to hospital with diarrhoea had an underlying malaria parasite infection (totaling 749 of 2,937 individuals, 26%). However, given the broad range of estimates, a paucity of purposeful case control or longitudinal studies, and varied or poorly specified definitions of diarrhoea, the literature provides limited evidence to draw any firm conclusions. The relationship between malaria and gastrointestinal disturbance thus remains unclear. Carefully designed case-control studies and prospective longitudinal studies are required to confidently assess the prevalence and significance of intestinal manifestations of malaria parasite infection.
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Affiliation(s)
- Isatou C M Sey
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Ajoke M Ehimiyein
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.,Department of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria
| | - Christian Bottomley
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Eleanor M Riley
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Jason P Mooney
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
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44
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Wu X, Thylur RP, Dayanand KK, Punnath K, Norbury CC, Gowda DC. IL-4 Treatment Mitigates Experimental Cerebral Malaria by Reducing Parasitemia, Dampening Inflammation, and Lessening the Cytotoxicity of T Cells. THE JOURNAL OF IMMUNOLOGY 2020; 206:118-131. [PMID: 33239419 DOI: 10.4049/jimmunol.2000779] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/28/2020] [Indexed: 12/22/2022]
Abstract
Cytokine responses to malaria play important roles in both protective immunity development and pathogenesis. Although the roles of cytokines such as TNF-α, IL-12, IFN-γ, and IL-10 in immunity and pathogenesis to the blood stage malaria are largely known, the role of IL-4 remains less understood. IL-4 targets many cell types and induces multiple effects, including cell proliferation, gene expression, protection from apoptosis, and immune regulation. Accordingly, IL-4 has been exploited as a therapeutic for several inflammatory diseases. Malaria caused by Plasmodium falciparum manifests in many organ-specific fatal pathologies, including cerebral malaria (CM), driven by a high parasite load, leading to parasite sequestration in organs and consequent excessive inflammatory responses and endothelial damage. We investigated the therapeutic potential of IL-4 against fatal malaria in Plasmodium berghei ANKA-infected C57BL/6J mice, an experimental CM model. IL-4 treatment significantly reduced parasitemia, CM pathology, and mortality. The therapeutic effect of IL-4 is mediated through multiple mechanisms, including enhanced parasite clearance mediated by upregulation of phagocytic receptors and increased IgM production, and decreased brain inflammatory responses, including reduced chemokine (CXCL10) production, reduced chemokine receptor (CXCR3) and adhesion molecule (LFA-1) expression by T cells, and downregulation of cytotoxic T cell lytic potential. IL-4 treatment markedly reduced the infiltration of CD8+ T cells and brain pathology. STAT6, PI3K-Akt-NF-κB, and Src signaling mediated the cellular and molecular events that contributed to the IL-4-dependent decrease in parasitemia. Overall, our results provide mechanistic insights into how IL-4 treatment mitigates experimental CM and have implications in developing treatment strategies for organ-specific fatal malaria.
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Affiliation(s)
- Xianzhu Wu
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Ramesh P Thylur
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Kiran K Dayanand
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Kishore Punnath
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Christopher C Norbury
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - D Channe Gowda
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; and
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45
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Apte SH, Minigo G, Groves PL, Spargo JC, Plebanski M, Grigg MJ, Kenangalem E, Burel JG, Loughland JR, Flanagan KL, Piera KA, William T, Price RN, Woodberry T, Barber BE, Anstey NM, Doolan DL. A population of CD4 hiCD38 hi T cells correlates with disease severity in patients with acute malaria. Clin Transl Immunology 2020; 9:e1209. [PMID: 33282291 PMCID: PMC7684974 DOI: 10.1002/cti2.1209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/08/2020] [Accepted: 10/20/2020] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVE CD4+ T cells are critical mediators of immunity to Plasmodium spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either P. falciparum or P. knowlesi malaria revealed a pronounced population of CD4+ T cells co-expressing very high levels of CD4 and CD38 we have termed CD4hiCD38hi T cells. We set out to gain insight into the function of these novel cells. METHODS CD4+ T cells from 18 patients with P. falciparum or P. knowlesi malaria were assessed by flow cytometry and sorted into populations of CD4hiCD38hi or CD4norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString. RESULTS CD4hiCD38hi T cells expressed high levels of CD4 mRNA and canonical type 1 regulatory T-cell (TR1) genes including IL10, IFNG, LAG3 and HAVCR2 (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials. CONCLUSION In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co-expression of CD4 and CD38 (CD4hiCD38hi) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T-cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria.
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Affiliation(s)
- Simon H Apte
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia,Present address:
Queensland Lung Transplant Service, The Prince Charles HospitalChermsideQLDAustralia
| | - Gabriela Minigo
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Penny L Groves
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia
| | - Jessie C Spargo
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Magdalena Plebanski
- Department of Immunology and PathologyMonash UniversityPrahranVICAustralia,School of Health and Biomedical SciencesRMIT UniversityBundooraVICAustralia
| | - Mathew J Grigg
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Enny Kenangalem
- Papuan Health and Community Development FoundationTimikaIndonesia
| | - Julie G Burel
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia,Present address:
La Jolla Institute for ImmunologyLa JollaCAUSA
| | - Jessica R Loughland
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia,Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Katie L Flanagan
- Department of Immunology and PathologyMonash UniversityPrahranVICAustralia,School of Health and Biomedical SciencesRMIT UniversityBundooraVICAustralia,School of MedicineUniversity of TasmaniaLauncestonTASAustralia
| | - Kim A Piera
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Timothy William
- School of MedicineUniversity of TasmaniaLauncestonTASAustralia
| | - Ric N Price
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Nuffield Department of Clinical MedicineCentre for Tropical Medicine and Global HealthUniversity of OxfordOxfordUK,Mahidol‐Oxford Tropical Medicine Research UnitFaculty of Tropical MedicineMahidol UniversityBangkokThailand
| | - Tonia Woodberry
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Bridget E Barber
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia,Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia,Charles Darwin UniversityDarwinNTAustralia
| | - Nicholas M Anstey
- Global and Tropical Health DivisionMenzies School of Health ResearchCasuarinaNTAustralia
| | - Denise L Doolan
- Infectious Diseases ProgramQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia,Centre for Molecular TherapeuticsAustralian Institute of Tropical Health & MedicineJames Cook UniversityCairnsQLDAustralia
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Kumar V, Ray S, Aggarwal S, Biswas D, Jadhav M, Yadav R, Sabnis SV, Banerjee S, Talukdar A, Kochar SK, Shetty S, Sehgal K, Patankar S, Srivastava S. Multiplexed quantitative proteomics provides mechanistic cues for malaria severity and complexity. Commun Biol 2020; 3:683. [PMID: 33204009 PMCID: PMC7672109 DOI: 10.1038/s42003-020-01384-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Management of severe malaria remains a critical global challenge. In this study, using a multiplexed quantitative proteomics pipeline we systematically investigated the plasma proteome alterations in non-severe and severe malaria patients. We identified a few parasite proteins in severe malaria patients, which could be promising from a diagnostic perspective. Further, from host proteome analysis we observed substantial modulations in many crucial physiological pathways, including lipid metabolism, cytokine signaling, complement, and coagulation cascades in severe malaria. We propose that severe manifestations of malaria are possibly underpinned by modulations of the host physiology and defense machinery, which is evidently reflected in the plasma proteome alterations. Importantly, we identified multiple blood markers that can effectively define different complications of severe falciparum malaria, including cerebral syndromes and severe anemia. The ability of our identified blood markers to distinguish different severe complications of malaria may aid in developing new clinical tests for monitoring malaria severity.
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Affiliation(s)
- Vipin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Sandipan Ray
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Shalini Aggarwal
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Deeptarup Biswas
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Manali Jadhav
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Radha Yadav
- Department of Mathematics, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Sanjeev V Sabnis
- Department of Mathematics, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Soumaditya Banerjee
- Medicine Department, Medical College Hospital Kolkata, 88, College Street, Kolkata, 700073, India
| | - Arunansu Talukdar
- Medicine Department, Medical College Hospital Kolkata, 88, College Street, Kolkata, 700073, India
| | - Sanjay K Kochar
- Department of Medicine, Malaria Research Centre, S.P. Medical College, Bikaner, 334003, India
| | - Suvin Shetty
- Dr. L H Hiranandani Hospital, Mumbai, 400076, India
| | | | - Swati Patankar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India.
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47
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Coban C. The host targeting effect of chloroquine in malaria. Curr Opin Immunol 2020; 66:98-107. [PMID: 32823144 PMCID: PMC7431399 DOI: 10.1016/j.coi.2020.07.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/21/2020] [Accepted: 07/21/2020] [Indexed: 01/07/2023]
Abstract
Due to the rapid onset and spread of the COVID-19 pandemic, the treatment of COVID-19 patients by hydroxychloroquine alone or in combination with other drugs has captured a great deal of attention and triggered considerable debate. Historically, the worldwide use of quinoline based-drugs has led to a spectacular reduction in death from malaria. Unfortunately, scientists have been forced to seek alternative drugs to treat malaria due to the emergence of chloroquine-resistant parasites in the 1960s. The repurposing of hydroxychloroquine against viral infections, various types of cancer and autoimmune diseases has been ongoing for more than 70 years, with no clear understanding of its mechanism of action (MOA). Here, we closely examine the MOA of this old but influential drug in and beyond malaria. Better insights into how chloroquine targets the host's cellular and immune responses may help to develop applications against to new pathogens and diseases, and perhaps even restore the clinical utility of chloroquine against malaria.
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Affiliation(s)
- Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan; Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
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48
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Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat Rev Immunol 2020; 21:137-150. [PMID: 32782357 PMCID: PMC7418297 DOI: 10.1038/s41577-020-0391-5] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence. The inducible responses of pattern recognition receptors of the innate immune system and antigen-specific receptors of the adaptive immune system are highly effective, but they also have the potential to cause extensive immunopathology and tissue damage, as seen in many infectious and autoinflammatory diseases. By contrast, constitutive innate immune mechanisms, including restriction factors, basal autophagy and proteasomal degradation, tend to limit immune responses, with loss-of-function mutations in these pathways leading to inflammation. Although they function through a broad and heterogeneous set of mechanisms, the constitutive immune responses all function as early barriers to infection and aim to minimize any disruption of homeostasis. Supported by recent human and mouse data, in this Review we compare and contrast the inducible and constitutive mechanisms of immunosurveillance.
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49
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Zhang Q, Ao Z, Hu N, Zhu Y, Liao F, Han D. Neglected interstitial space in malaria recurrence and treatment. NANO RESEARCH 2020; 13:2869-2878. [PMID: 32837694 PMCID: PMC7378403 DOI: 10.1007/s12274-020-2946-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/15/2020] [Accepted: 06/19/2020] [Indexed: 05/30/2023]
Abstract
The interstitial space, a widespread fluid-filled compartment throughout the body, is related to many pathophysiological alterations and diseases, attracting increasing attention. The vital role of interstitial space in malaria infection and treatment has been neglected current research efforts. We confirmed the reinfection capacity of parasites sequestrated in interstitial space, which replenish the mechanism of recurrence. Malaria parasite-infected mice were treated with artemisinin-loaded liposomes through the interstitial space and exhibited a better therapeutic response. Notably, compared with oral administration, interstitial administration showed an unexpectedly high activation and recruitment of immune cells, and resulted in better clearance of sequestered parasites from organs, and enhanced pathological recovery. The interstitial route of administration prolongs the blood circulation time of artemisinin and increases its plasma concentration, and may compensate for the inefficiency of oral administration and the nanotoxicity of intravenous administration, providing a potential strategy for infectious disease therapy.
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Affiliation(s)
- Qiang Zhang
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Zhuo Ao
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Nan Hu
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
- Department of Traditional Chinese Medicine, Chengde Medical University, Chengde, 066000 China
| | - Yuting Zhu
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
| | - Fulong Liao
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
- Artemisinin Research Center and the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100049 China
| | - Dong Han
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
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50
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Golenser J, Salaymeh N, Higazi AA, Alyan M, Daif M, Dzikowski R, Domb AJ. Treatment of Experimental Cerebral Malaria by Slow Release of Artemisone From Injectable Pasty Formulation. Front Pharmacol 2020; 11:846. [PMID: 32595499 PMCID: PMC7303303 DOI: 10.3389/fphar.2020.00846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 05/22/2020] [Indexed: 12/26/2022] Open
Abstract
Malaria caused by Plasmodium falciparum causes numerous cases of morbidity with about 400,000 deaths yearly owing, mainly, to inflammation leading to cerebral malaria (CM). CM conventionally is treated by repetitive administration of anti-plasmodial drugs and supportive non-specific drugs, for about a week. A mouse model of CM caused by Plasmodium berghei ANKA, in which brain and systemic clinical pathologies occur followed by sudden death within about a week, was used to study the effect of artemisone, a relatively new artemisinin, within an injectable pasty polymer formulated for its controlled release. The parasites were exposed to the drug over several days at a non-toxic concentrations for the mice but high enough to affect the parasites. Artemisone was also tested in cultures of bacteria, cancer cells and P. falciparum to evaluate the specificity and suitability of these cells for examining the release of artemisone from its carrier. Cultures of P. falciparum were the most suitable. Artemisone released from subcutaneous injected poly(sebacic acid-ricinoleic acid) (PSARA) pasty polymer, reduced parasitemias in infected mice, prolonged survival and prevented death in most of the infected mice. Successful prophylactic treatment before infection proved that there was a slow release of the drug for about a week, which contrasts with the three hour half-life that occurs after injection of just the drug. Treatment with artemisone within the polymer, even at a late stage of the disease, helped to prevent or, at least, delay accompanying severe symptoms. In some cases, treatment prevented death of CM and the mice died later of anemia. Postponing the severe clinical symptoms is also beneficial in cases of human malaria, giving more time for an appropriate diagnosis and treatment before severe symptoms appear. The method presented here may also be useful for combination therapy of anti-plasmodial and immunomodulatory drugs.
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Affiliation(s)
- Jacob Golenser
- Department of Microbiology and Molecular Genetics, The Kuvin Centre for the Study of Infectious and Tropical Diseases, Faculty of Medicine, the Hebrew University (HU), Jerusalem, Israel
| | - Nadeen Salaymeh
- Department of Microbiology and Molecular Genetics, The Kuvin Centre for the Study of Infectious and Tropical Diseases, Faculty of Medicine, the Hebrew University (HU), Jerusalem, Israel
| | | | - Mohammed Alyan
- Department of Microbiology and Molecular Genetics, The Kuvin Centre for the Study of Infectious and Tropical Diseases, Faculty of Medicine, the Hebrew University (HU), Jerusalem, Israel
- Faculty of Medicine, School of Pharmacy, Institute of Drug Research, HU, Jerusalem, Israel
| | - Mahran Daif
- Faculty of Medicine, School of Pharmacy, Institute of Drug Research, HU, Jerusalem, Israel
| | - Ron Dzikowski
- Department of Microbiology and Molecular Genetics, The Kuvin Centre for the Study of Infectious and Tropical Diseases, Faculty of Medicine, the Hebrew University (HU), Jerusalem, Israel
| | - Abraham J. Domb
- Faculty of Medicine, School of Pharmacy, Institute of Drug Research, HU, Jerusalem, Israel
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