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Sukati S, Rattanatham R, Masangkay FR, Tseng CP, Kotepui M. Alterations in von Willebrand Factor Levels in Patients with Malaria: A Systematic Review and Meta-Analysis of Disease Severity. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:767. [PMID: 40283058 PMCID: PMC12028635 DOI: 10.3390/medicina61040767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Elevated von Willebrand factor (vWF) levels have been reported in malaria, but their relationship with disease severity remains unclear. This study aimed to compare vWF levels between Plasmodium-infected and uninfected individuals and assess changes in severe infections. Materials and Methods: The systematic review was registered in PROSPERO (CRD42024558479). A comprehensive search across six databases identified studies reporting vWF levels in malaria. A meta-analysis was conducted using a random-effects model, with standardized mean difference (SMD) as the effect measure due to varying measurement units. Heterogeneity was assessed using the I2 statistic. Results: Of 1647 identified records, 26 studies met the inclusion criteria. The meta-analysis showed significantly higher vWF levels in Plasmodium-infected individuals compared to uninfected controls (p < 0.001, SMD: 2.689 [95% CI 1.362; 4.017], I2: 98.1%, 12 studies, 3109 participants). However, no significant difference was found between severe and less severe cases (p = 0.051, SMD: 3.551 [95% CI -0.007; 7.109], I2: 99.3%, 8 studies, 1453 participants). Conclusions: vWF levels are significantly elevated in individuals with Plasmodium infections, indicating a potential role in malaria pathophysiology. Although levels tend to be higher in severe cases, current evidence is insufficient to support vWF as a reliable marker for disease severity. Further prospective and well-controlled studies are needed to validate its diagnostic and prognostic value in malaria management.
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Affiliation(s)
- Suriyan Sukati
- Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat 80160, Thailand;
- Hematology and Transfusion Science Research Center, Walailak University, Tha Sala, Nakhon Si Thammarat 80160, Thailand
| | - Rujikorn Rattanatham
- Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand
| | | | - Ching-Ping Tseng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Manas Kotepui
- Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand
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Blick-Nitko SK, Ture SK, Schafer XL, Munger JC, Livada AC, Li C, Maurya P, Rondina MT, Morrell CN. Platelet Ido1 expression is induced during Plasmodium yoelii infection, altering plasma tryptophan metabolites. Blood Adv 2024; 8:5814-5825. [PMID: 39133890 PMCID: PMC11609358 DOI: 10.1182/bloodadvances.2024013175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/24/2024] [Accepted: 07/24/2024] [Indexed: 11/11/2024] Open
Abstract
ABSTRACT Platelets are immune responsive in many diseases as noted by changes in platelet messenger RNA in conditions such as sepsis, atherosclerosis, COVID-19, and many other inflammatory and infectious etiologies. The malaria causing Plasmodium parasite is a persistent public health threat and significant evidence shows that platelets participate in host responses to infection. Using a mouse model of nonlethal/uncomplicated malaria, non-lethal Plasmodium yoelii strain XNL (PyNL)-infected but not control mouse platelets expressed Ido1, a rate limiting enzyme in tryptophan metabolism that increases kynurenine at the expense of serotonin. Interferon-γ (IFN-γ) is a potent inducer of Ido1 and mice treated with recombinant IFN-γ had increased platelet Ido1 and IDO1 activity. PyNL-infected mice treated with anti-IFN-γ antibody had similar platelet Ido1 and metabolic profiles to that of uninfected controls. PyNL-infected mice become thrombocytopenic by day 7 after infection and transfusion of platelets from IFN-γ-treated wild-type mice but not Ido1-/- mice increased the plasma kynurenine-to-tryptophan ratio, indicating that platelets are a source of postinfection IDO1 activity. We generated platelet-specific Ido1 knockout mice to assess the contribution of platelet Ido1 during PyNL infection. Platelet-specific Ido1-/- mice had increased death and evidence of lung thrombi, which were not present in infected wild-type mice. Platelet Ido1 may be a significant contributor to plasma kynurenine in IFN-γ-driven immune processes and the loss of platelets may limit total Ido1, leading to immune and vascular dysfunction.
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Affiliation(s)
- Sara K. Blick-Nitko
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Sara K. Ture
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Xenia L. Schafer
- Department of Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Joshua C. Munger
- Department of Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Alison C. Livada
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Chen Li
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Preeti Maurya
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | | | - Craig N. Morrell
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY
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Abdelfattah A, Hijjawi NS, Jacoub K. An overview of qualitative and quantitative platelet abnormalities in schistosomiasis. Parasitol Res 2024; 123:225. [PMID: 38809265 DOI: 10.1007/s00436-024-08245-7] [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: 03/19/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Schistosomiasis is a neglected tropical disease referring to the infection with blood parasitic trematodes of the genus Schistosoma. It impacts millions of people worldwide, primarily in low-to-middle-income countries. Patients infected with schistosomiasis often exhibit a distinct hematological profile, including anemia, eosinophilia, thrombocytopenia, and coagulopathy. Platelets, essential components of the hemostatic system, play a crucial role in the pathogenesis of schistosomiasis. Schistosomes secrete serine proteases and express ectoenzymes, such as calpain protease, alkaline phosphatase (SmAP), phosphodiesterase (SmNPP5), ATP diphosphohydrolase (SmATPDase1), serine protease Sk1, SmSP2, and Sm22.6, which can interfere with platelet normal functioning. This report provides comprehensive, up-to-date information on platelet abnormalities observed in patients with schistosomiasis, highlighting their importance in the disease progression and complications. It delves into the interactions between platelets and schistosomes, including the impact of platelet dysfunction on hemostasis and immune responses, immune-mediated platelet destruction, and the potential mechanisms by which schistosome tegumental ectoenzymes affect platelets. Furthermore, the report clarifies the relationship between platelet abnormalities and clinical manifestations such as thrombocytopenia, coagulation disorders, and the emergence of portal hypertension and gastrointestinal bleeding. Understanding the complex interplay between platelets and schistosomes is crucial for improving patient management and outcomes in schistosomiasis, particularly for those with platelet alterations. This knowledge contributes to improved diagnostic methods, innovative treatment strategies, and global efforts to control and eliminate schistosomiasis.
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Affiliation(s)
- Ali Abdelfattah
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan.
| | - Nawal S Hijjawi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan
| | - Khaldun Jacoub
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan
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Howell MM, Olajiga OM, Cardenas JC, Parada-Higuera CA, Gonzales-Pabon MU, Gutierrez-Silva LY, Jaimes-Villamizar L, Werner BM, Shaffer JG, Manuzak JA, Londono-Renteria B. Mosquito Salivary Antigens and Their Relationship to Dengue and P. vivax Malaria. Pathogens 2024; 13:52. [PMID: 38251359 PMCID: PMC10818852 DOI: 10.3390/pathogens13010052] [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: 10/31/2023] [Revised: 12/10/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
In tropical areas, the simultaneous transmission of multiple vector-borne diseases is common due to ecological factors shared by arthropod vectors. Malaria and dengue virus, transmitted by Anopheles and Aedes mosquitoes, respectively, are among the top vector-borne diseases that cause significant morbidity and mortality in endemic areas. Notably, tropical areas often have suitable conditions for the co-existence of these mosquito species, highlighting the importance of identifying markers that accurately indicate the risk of acquiring each specific disease entity. Aedes are daytime-biting mosquitoes, while Anopheles preferentially bite during the night. These biting patterns raise the possibility of concurrent exposure to bites from both species. This is important because mosquito saliva, deposited in the skin during blood feeding, induces immune responses that modulate pathogen establishment and infection. Previous studies have focused on characterizing such effects on the vector-pathogen interface for an individual pathogen and its mosquito vector. In this study, we evaluated associations between immune responses to salivary proteins from non-dengue and non-malaria vector mosquito species with clinical characteristics of malaria and dengue, respectively. Surprisingly, antibody responses against Anopheles antigens in dengue patients correlated with red blood cell count and hematocrit, while antibody responses against Aedes proteins were associated with platelet count in malaria patients. Our data indicate that concurrent exposure to multiple disease-carrying mosquito vectors and their salivary proteins with differing immunomodulatory properties could influence the transmission, pathogenesis, and clinical presentation of malaria, dengue fever, and other vector-borne illnesses.
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Affiliation(s)
- McKenna M. Howell
- Arbovirology Laboratory, Department of Tropical Medicine and Infectious Disease, Tulane University, New Orleans, LA 70112, USA; (M.M.H.); (J.C.C.)
| | - Olayinka M. Olajiga
- Arbovirology Laboratory, Department of Tropical Medicine and Infectious Disease, Tulane University, New Orleans, LA 70112, USA; (M.M.H.); (J.C.C.)
| | - Jenny C. Cardenas
- Arbovirology Laboratory, Department of Tropical Medicine and Infectious Disease, Tulane University, New Orleans, LA 70112, USA; (M.M.H.); (J.C.C.)
| | | | | | | | | | - Brett M. Werner
- College of Science and Technology, Bellevue University, Bellevue, NE 68005, USA;
| | - Jeffrey G. Shaffer
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA;
| | - Jennifer A. Manuzak
- Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA;
| | - Berlin Londono-Renteria
- Arbovirology Laboratory, Department of Tropical Medicine and Infectious Disease, Tulane University, New Orleans, LA 70112, USA; (M.M.H.); (J.C.C.)
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Asmerom H, Gemechu K, Sileshi B, Arkew M. Hematological Abnormalities Among Malaria Infected Adult Patients in Association with ABO Blood Groups at Jinella Health Center, Harar, Eastern Ethiopia. J Blood Med 2023; 14:463-476. [PMID: 37638257 PMCID: PMC10457518 DOI: 10.2147/jbm.s419815] [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: 05/04/2023] [Accepted: 08/11/2023] [Indexed: 08/29/2023] Open
Abstract
Background Hematological abnormalities are a common complication of malaria infection. However, there is a paucity of evidence regarding it among malaria-infected adult patients in association with the ABO blood group in Ethiopia, particularly in the Harari Region. Therefore, this study aimed to assess the hematological abnormalities among malaria-infected adult patients in association with ABO blood groups at Jinella Health Center, Harar, Eastern Ethiopia. Methods An institutional-based cross-sectional study was conducted from July 10, 2022, to January 10, 2023. Four milliliters of venous blood were collected from each study participant. Drops of blood were used for blood film preparation. ABO blood group was determined by agglutination test using monoclonal anti-sera (Agape Diagnostics Ltd., India). A complete blood count was done using the DxH 800 (Beckman Coulter, Inc, Miami, FL) hematology analyzer. The data were analyzed using SPSS version 26. Bivariable and multivariable logistic regression models were fitted. The level of significance was declared at a p-value of <0.05. Results The study revealed that 47.2% (95% CI: 41.0 53.6) of the participants were anemic. Being female (AOR = 3.18, 95% CI = 1.67, 6.04), having the A blood group (AOR = 2.75, CI = 1.20, 6.31), and being infected with P. falciparum (AOR = 2.64, CI = 1.26, 5.53) were all significantly associated with malaria anemia. The overall prevalence of thrombocytopenia was also 67.7% (95% CI: 61.7-73.4%). It was significantly associated with P. falciparum infection (AOR = 8.03, CI = 3.53, 18.25) and high parasitemia levels (AOR = 4.40, CI = 1.57, 12.32). Conclusion Patients with malaria who belonged to the "A" blood group in the study area had anemia as a serious health problem. Hence, frequently checking for anemia in patients with malaria who have blood group "A" can help with early detection and better management of anemia.
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Affiliation(s)
- Haftu Asmerom
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Kabtamu Gemechu
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Beza Sileshi
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Mesay Arkew
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
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Kong D, Tan R, Gao Y, Gao S, Feng Z, Qi H, Shen B, Yang L, Shen X, Jing X, Zhao X. Arterial Baroreflex Dysfunction Promotes Neuroinflammation by Activating the Platelet CD40L/Nuclear Factor Kappa B Signaling Pathway in Microglia and Astrocytes. Neurochem Res 2023; 48:1691-1706. [PMID: 36592325 PMCID: PMC10119255 DOI: 10.1007/s11064-022-03852-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023]
Abstract
Arterial baroreflex (ABR) dysfunction has previously been associated with neuroinflammation, the most common pathological feature of neurological disorders. However, the mechanisms mediating ABR dysfunction-induced neuroinflammation are not fully understood. In the present study, we investigated the role of platelet CD40 ligand (CD40L) in neuroinflammation in an in vivo model of ABR dysfunction, and microglia and astrocyte activation in vitro. ABR dysfunction was induced in Sprague‒Dawley rats by sinoaortic denervation (SAD). We used ELSA and immunofluorescence to assess the effect of platelet CD40L on glial cell polarization and the secretion of inflammatory factors. By flow cytometry, we found that rats subjected to SAD showed a high level of platelet microaggregation and upregulation of CD40L on the platelet surface. The promotion of platelet invasion and accumulation was also observed in the brain tissues of rats subjected to SAD. In the animal model and cultured N9 microglia/C6 astrocytoma cells, platelet CD40L overexpression promoted neuroinflammation and activated M1 microglia, A1 astrocytes, and the nuclear factor kappa B (NFκB) signaling pathway. These effects were partially blocked by inhibiting platelet activity with clopidogrel or inhibiting CD40L-mediated signaling. Our results suggest that during ABR dysfunction, CD40L signaling in platelets converts microglia to the M1 phenotype and astrocytes to the A1 phenotype, activating NFκB and resulting in neuroinflammation. Thus, our study provides a novel understanding of the pathogenesis of ABR dysfunction-induced neuroinflammation and indicates that targeting platelet CD40L is beneficial for treating central nervous system (CNS) disorders associated with ABR dysfunction.
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Affiliation(s)
- Deping Kong
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Rui Tan
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Yongfeng Gao
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Shan Gao
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Zhaoyang Feng
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Huibin Qi
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Bowen Shen
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Lili Yang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Xuri Shen
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China
| | - Xiuli Jing
- School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, 271016, Tai'an, China
| | - Xiaomin Zhao
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 619 Changcheng Road, 271016, Tai'an, People's Republic of China.
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Pathogenesis of Anemia in Canine Babesiosis: Possible Contribution of Pro-Inflammatory Cytokines and Chemokines-A Review. Pathogens 2023; 12:pathogens12020166. [PMID: 36839438 PMCID: PMC9962459 DOI: 10.3390/pathogens12020166] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Canine babesiosis is a tick-borne protozoan disease caused by intraerythrocytic parasites of the genus Babesia. The infection may lead to anemia in infected dogs. However, anemia is not directly caused by the pathogen. The parasite's developmental stages only have a marginal role in contributing to a decreased red blood cell (RBC) count. The main cause of anemia in affected dogs is the immune response to the infection. This response includes antibody production, erythrophagocytosis, oxidative damage of RBCs, complement activation, and antibody-dependent cellular cytotoxicity. Moreover, both infected and uninfected erythrocytes are retained in the spleen and sequestered in micro-vessels. All these actions are driven by pro-inflammatory cytokines and chemokines, especially IFN-γ, TNF-α, IL-6, and IL-8. Additionally, imbalance between the actions of pro- and anti-inflammatory cytokines plays a role in patho-mechanisms leading to anemia in canine babesiosis. This article is a review of the studies on the pathogenesis of anemia in canine babesiosis and related diseases, such as bovine or murine babesiosis and human or murine malaria, and the role of pro-inflammatory cytokines and chemokines in the mechanisms leading to anemia in infected dogs.
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Asmerom H, Gemechu K, Bete T, Sileshi B, Gebremichael B, walle M, Arkew M. Platelet Parameters and Their Correlation with Parasitemia Levels Among Malaria Infected Adult Patients at Jinella Health Center, Harar, Eastern Ethiopia: Comparative Cross-Sectional Study. J Blood Med 2023; 14:25-36. [PMID: 36698775 PMCID: PMC9869896 DOI: 10.2147/jbm.s394704] [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: 10/24/2022] [Accepted: 01/12/2023] [Indexed: 01/20/2023] Open
Abstract
Background Malaria is a major public health problem with the highest morbidity and mortality in developing countries. Hematological changes play a great role in malaria pathogenesis through platelets and platelet parameters. However, the changes in platelet parameters are not clearly described in Ethiopia. Therefore, this study aimed to compare platelet parameters and their correlation with parasitemia among malaria-infected adult patients and healthy adults. Methods An institutional-based comparative cross-sectional study was conducted involving 186 (93 malaria-infected patients and 93 healthy adults) study participants using a convenient sampling technique at Jinella health center, Harar, Eastern Ethiopia, from July 10-August 10, 2022. Five milliliters of venous blood were collected from each study participant, and platelet parameters were analyzed using a Unicel (DxH 800) automated hematologic analyzer. A drop of blood was taken from malaria-suspected patients for blood film preparation. Results between two groups were compared using the Mann-Whitney U-test. Spearman's rank correlation coefficient was used to evaluate the relationships between two continuous variables. A P-value of < 0.05 was considered statistically significant. Results Platelet, plateletcrit, and mean platelet volume of malaria-infected patients were significantly lower as compared with healthy adults (103 x103cells/μL vs 268 x103cells/μL, 0.13 fl vs 0.23 fl, and 9.6 fl vs 15.3 fl), respectively). Conversely, platelet distribution width and platelet large cell ratio were higher in malaria-infected patients than healthy adults (19.2% vs 15.3% and 0.35% vs 0.29%), respectively). Parasitemia levels had a moderately inverse correlation with platelet count (r= -0.419) and a weakly positive correlation with mean platelet volume (r=0.278). Conclusion The platelet, plateletcrit, and mean platelet volume of malaria-infected patients were significantly lower as compared with healthy adults. Malaria parasitemia had a moderate inverse correlation with platelet count and a weak positive correlation with mean platelet volume. Thrombocytopenia and alteration of platelet parameters should be considered in malaria patients.
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Affiliation(s)
- Haftu Asmerom
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Kabtamu Gemechu
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Tilahun Bete
- School of Nursing and Midwifery, Department of Psychiatry, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Beza Sileshi
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Berhe Gebremichael
- School of Public Health, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Muluken walle
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Jigjiga University, Jigjiga, Ethiopia
| | - Mesay Arkew
- School of Medical Laboratory Sciences, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
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9
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He Z, Yu C, Pan Z, Li X, Zhang X, Huang Q, Liao X, Hu J, Zeng F, Ru L, Yu W, Xu Q, Song J, Liang J. Erythrocyte membrane with CLIPPKF as biomimetic nanodecoy traps merozoites and attaches to infected red blood cells to prevent Plasmodium infection. J Nanobiotechnology 2023; 21:15. [PMID: 36647056 PMCID: PMC9841648 DOI: 10.1186/s12951-022-01709-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 11/14/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Malaria remains a serious threat to global public health. With poor efficacies of vaccines and the emergence of drug resistance, novel strategies to control malaria are urgently needed. RESULTS We developed erythrocyte membrane-camouflaged nanoparticles loaded with artemether based on the growth characteristics of Plasmodium. The nanoparticles could capture the merozoites to inhibit them from repeatedly infecting normal erythrocytes, owing to the interactions between merozoites and heparin-like molecules on the erythrocyte membrane. Modification with a phosphatidylserine-targeting peptide (CLIPPKF) improved the drug accumulation in infected red blood cells (iRBCs) from the externalized phosphatidylserine induced by Plasmodium infection. In Plasmodium berghei ANKA strain (pbANKA)-infected C57BL/6 mice, the nanoparticles significantly attenuated Plasmodium-induced inflammation, apoptosis, and anemia. We observed reduced weight variation and prolonged survival time in pbANKA-challenged mice, and the nanoparticles showed good biocompatibility and negligible cytotoxicity. CONCLUSION Erythrocyte membrane-camouflaged nanoparticles loaded with artemether were shown to provide safe and effective protection against Plasmodium infection.
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Affiliation(s)
- Zhouqing He
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Chuyi Yu
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Ziyi Pan
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Xiaobo Li
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Xiangxiang Zhang
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Qijing Huang
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Xingcheng Liao
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Jiaoting Hu
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Feng Zeng
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Li Ru
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Wanlin Yu
- grid.413402.00000 0004 6068 0570Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120 China
| | - Qin Xu
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Jianping Song
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
| | - Jianming Liang
- grid.411866.c0000 0000 8848 7685Artemisinin Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405 China ,grid.8547.e0000 0001 0125 2443Key Laboratory of Smart Drug Delivery, School of Pharmacy, Ministry of Education, Fudan University, Shanghai, 201203 China
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10
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Akide Ndunge OB, Kilian N, Salman MM. Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202944. [PMID: 36300890 PMCID: PMC9798991 DOI: 10.1002/advs.202202944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/22/2022] [Indexed: 06/01/2023]
Abstract
Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria.
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Affiliation(s)
- Oscar Bate Akide Ndunge
- Department of Internal MedicineSection of Infectious DiseasesYale University School of Medicine300 Cedar StreetNew HavenCT06510USA
| | - Nicole Kilian
- Centre for Infectious Diseases, ParasitologyHeidelberg University HospitalIm Neuenheimer Feld 32469120HeidelbergGermany
| | - Mootaz M. Salman
- Department of PhysiologyAnatomy and GeneticsUniversity of OxfordOxfordOX1 3QUUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
- Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUK
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11
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Song X, Wei W, Cheng W, Zhu H, Wang W, Dong H, Li J. Cerebral malaria induced by plasmodium falciparum: clinical features, pathogenesis, diagnosis, and treatment. Front Cell Infect Microbiol 2022; 12:939532. [PMID: 35959375 PMCID: PMC9359465 DOI: 10.3389/fcimb.2022.939532] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Cerebral malaria (CM) caused by Plasmodium falciparum is a fatal neurological complication of malaria, resulting in coma and death, and even survivors may suffer long-term neurological sequelae. In sub-Saharan Africa, CM occurs mainly in children under five years of age. Although intravenous artesunate is considered the preferred treatment for CM, the clinical efficacy is still far from satisfactory. The neurological damage induced by CM is irreversible and lethal, and it is therefore of great significance to unravel the exact etiology of CM, which may be beneficial for the effective management of this severe disease. Here, we review the clinical characteristics, pathogenesis, diagnosis, and clinical therapy of CM, with the aim of providing insights into the development of novel tools for improved CM treatments.
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Affiliation(s)
- Xiaonan Song
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Wei Wei
- Beijing School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing, China
| | - Weijia Cheng
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Huiyin Zhu
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Wei Wang
- Key Laboratory of National Health Commission on Technology for Parasitic Diseases Prevention and Control, Jiangsu Provincial Key Laboratory on Parasites and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Haifeng Dong
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, China
| | - Jian Li
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
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12
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Cox D. Targeting SARS-CoV-2-Platelet Interactions in COVID-19 and Vaccine-Related Thrombosis. Front Pharmacol 2021; 12:708665. [PMID: 34290613 PMCID: PMC8287727 DOI: 10.3389/fphar.2021.708665] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/24/2021] [Indexed: 01/08/2023] Open
Abstract
It is clear that COVID-19 is more than a pneumonia and is associated with a coagulopathy and multi-organ failure. While the use of anti-coagulants does reduce the incidence of pulmonary emboli, it does not help with survival. This suggests that the coagulopathy is more likely to be platelet-driven rather than thrombin-driven. There is significant evidence to suggest that SARS-CoV-2 virions directly interact with platelets to trigger activation leading to thrombocytopenia and thrombosis. I propose a model of multiple interactions between SARS-CoV-2 and platelets that has many similarities to that with Staphylococcus aureus and Dengue virus. As platelet activation and thrombosis are major factors in poor prognosis, therapeutics that target the platelet-SARS-CoV-2 interaction have potential in treating COVID-19 and other virus infections.
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Affiliation(s)
- Dermot Cox
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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13
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Jongruamklang P, Rebetz J, Kapur R, Persson KEM, Olsson ML, Semple JW, Storry JR. Platelets inhibit erythrocyte invasion by Plasmodium falciparum at physiological platelet:erythrocyte ratios. Transfus Med 2021; 32:168-174. [PMID: 33987889 DOI: 10.1111/tme.12791] [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: 02/21/2020] [Revised: 10/05/2020] [Accepted: 12/27/2020] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To evaluate the effect of platelet:erythrocyte (P:E) ratios on Plasmodium falciparum erythrocyte invasion. BACKGROUND Recent reports have shown that platelets are directly involved in the immune response towards P. falciparum during erythrocyte invasion. However, the literature both supports and conflicts with a role for platelets in limiting invasion. Also, the effect of platelet numbers on invasion (parasitemia) has not been thoroughly investigated. METHODS/MATERIALS The P. falciparum strains FCR3S1.2 and W2mef were cultured with group O erythrocytes. The cultures were synchronised and supplemented with pooled platelets at P:E ratios ranging from 1:100 to 1:2. Parasitemia was measured at 40 h by flow cytometry and by microscopy of blood smears. RESULTS A linear relationship was observed between reduced invasion and increased platelet numbers at P:E ratios ranging from 1:100 to 1:20. However, this effect was reversed at lower ratios (1:10-1:2). Microscopic evaluation revealed aggregation and attachment of platelets to erythrocytes, but not specifically to parasitised erythrocytes. CONCLUSION We have shown that under physiological P:E ratios (approx. 1:10-1:40), platelets inhibited P. falciparum invasion in a dose-dependent manner. At ratios of 1:10 and below, platelets did not further increase the inhibitory effect and, although the trend was reversed, inhibition was still maintained.
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Affiliation(s)
- Philaiphon Jongruamklang
- Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.,Department of Medical Technology, School of Allied Health Sciences, University of Phayao, Phayao, Thailand
| | - Johan Rebetz
- Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden
| | - Rick Kapur
- Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands.,Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Kristina E M Persson
- Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, Lund, Sweden.,Clinical Chemistry and Pharmacology, Laboratory Medicine, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Martin L Olsson
- Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.,Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office for Medical Services, Region Skåne, Lund, Sweden
| | - John W Semple
- Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.,Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Jill R Storry
- Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.,Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office for Medical Services, Region Skåne, Lund, Sweden
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14
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Kraisin S, Martinod K, Desender L, Pareyn I, Verhenne S, Deckmyn H, Vanhoorelbeke K, Van den Steen PE, De Meyer SF. von Willebrand factor increases in experimental cerebral malaria but is not essential for late-stage pathogenesis in mice. J Thromb Haemost 2020; 18:2377-2390. [PMID: 32485089 DOI: 10.1111/jth.14932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/24/2020] [Accepted: 05/19/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Cerebral malaria (CM) is the most severe complication of malaria. Endothelial activation, cytokine release, and vascular obstruction are essential hallmarks of CM. Clinical studies have suggested a link between von Willebrand factor (VWF) and malaria pathology. OBJECTIVES To investigate the contribution of VWF in the pathogenesis of experimental cerebral malaria (ECM). METHODS Both Vwf+/+ and Vwf-/- mice were infected with Plasmodium berghei ANKA (PbANKA) to induce ECM. Alterations of plasma VWF and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), platelet count, neurological features, and accumulation of platelets and leukocytes in the brain were examined following infection. RESULTS Plasma VWF levels significantly increased upon PbANKA infection in Vwf+/+ animals. While ADAMTS13 activity was not affected, high molecular weight VWF multimers disappeared at the end-stage ECM, possibly due to an ongoing hypercoagulability. Although the number of reticulocytes, a preferential target for the parasites, was increased in Vwf-/- mice compared to Vwf+/+ mice early after infection, parasitemia levels did not markedly differ between the two groups. Interestingly, Vwf-/- mice manifested overall clinical ECM features similar to those observed in Vwf+/+ animals. At day 8.5 post-infection, however, clinical ECM features in Vwf-/- mice were slightly more beneficial than in Vwf+/+ animals. Despite these minor differences, overall survival was not different between Vwf-/- and Vwf+/+ mice. Similarly, PbANKA-induced thrombocytopenia, leukocyte, and platelet accumulations in the brain were not altered by the absence of VWF. CONCLUSIONS Our study suggests that increased VWF concentration is a hallmark of ECM. However, VWF does not have a major influence in modulating late-stage ECM pathogenesis.
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Affiliation(s)
- Sirima Kraisin
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Kimberly Martinod
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
- Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Linda Desender
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Inge Pareyn
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Sebastien Verhenne
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Hans Deckmyn
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Philippe E Van den Steen
- Laboratory of Immunoparasitology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Simon F De Meyer
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
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15
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Rodríguez AM, Trotta A, Melnyczajko AP, Miraglia MC, Kim KS, Delpino MV, Barrionuevo P, Giambartolomei GH. Brucella abortus-Stimulated Platelets Activate Brain Microvascular Endothelial Cells Increasing Cell Transmigration through the Erk1/2 Pathway. Pathogens 2020; 9:708. [PMID: 32867217 PMCID: PMC7558107 DOI: 10.3390/pathogens9090708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/14/2020] [Accepted: 08/25/2020] [Indexed: 01/18/2023] Open
Abstract
Central nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. A common feature associated with this pathology is blood-brain barrier (BBB) activation. However, the underlying mechanisms involved with such BBB activation remain unknown. The aim of this work was to investigate the role of Brucella abortus-stimulated platelets on human brain microvascular endothelial cell (HBMEC) activation. Platelets enhanced HBMEC activation in response to B. abortus infection. Furthermore, supernatants from B. abortus-stimulated platelets also activated brain endothelial cells, inducing increased secretion of IL-6, IL-8, CCL-2 as well as ICAM-1 and CD40 upregulation on HBMEC compared with supernatants from unstimulated platelets. Outer membrane protein 19, a B. abortus lipoprotein, recapitulated B. abortus-mediated activation of HBMECs by platelets. In addition, supernatants from B. abortus-activated platelets promoted transendothelial migration of neutrophils and monocytes. Finally, using a pharmacological inhibitor, we demonstrated that the Erk1/2 pathway is involved in the endothelial activation induced by B. abortus-stimulated platelets and also in transendothelial migration of neutrophils. These results describe a mechanism whereby B. abortus-stimulated platelets induce endothelial cell activation, promoting neutrophils and monocytes to traverse the BBB probably contributing to the inflammatory pathology of neurobrucellosis.
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Affiliation(s)
- Ana María Rodríguez
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1120AAD, Argentina; (A.M.R.); (A.P.M.); (M.C.M.); (M.V.D.)
| | - Aldana Trotta
- Instituto de Medicina Experimental (IMEX) (CONICET-Academia Nacional de Medicina), Buenos Aires C1425ASU, Argentina; (A.T.); (P.B.)
| | - Agustina P. Melnyczajko
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1120AAD, Argentina; (A.M.R.); (A.P.M.); (M.C.M.); (M.V.D.)
| | - M. Cruz Miraglia
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1120AAD, Argentina; (A.M.R.); (A.P.M.); (M.C.M.); (M.V.D.)
| | - Kwang Sik Kim
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
| | - M. Victoria Delpino
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1120AAD, Argentina; (A.M.R.); (A.P.M.); (M.C.M.); (M.V.D.)
| | - Paula Barrionuevo
- Instituto de Medicina Experimental (IMEX) (CONICET-Academia Nacional de Medicina), Buenos Aires C1425ASU, Argentina; (A.T.); (P.B.)
| | - Guillermo Hernán Giambartolomei
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1120AAD, Argentina; (A.M.R.); (A.P.M.); (M.C.M.); (M.V.D.)
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16
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Costa AG, Chaves YO, Teixeira-Carvalho A, Ramasawmy R, Antonelli LRV, Barbosa L, Balieiro A, Monteiro WM, Mourão MP, Lacerda MVG, Martins-Filho OA, Costa FTM, Malheiro A, Nogueira PA. Increased platelet distribution width and reduced IL-2 and IL-12 are associated with thrombocytopenia in Plasmodium vivax malaria. Mem Inst Oswaldo Cruz 2020; 115:e200080. [PMID: 32696915 PMCID: PMC7367212 DOI: 10.1590/0074-02760200080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 06/26/2020] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Thrombocytopenia in malaria involves platelet destruction and consumption; however, the cellular response underlying this phenomenon has still not been elucidated. OBJECTIVE To find associations between platelet indices and unbalanced Th1/Th2/Th17 cytokines as a response to thrombocytopenia in Plasmodium vivax infected (Pv-MAL) patients. METHODS Platelet counts and quantification of Th1/Th2/Th17 cytokine levels were compared in 77 patients with uncomplicated P. vivax malaria and 37 healthy donors from the same area (endemic control group - ENCG). FINDINGS Thrombocytopenia was the main manifestation in 55 patients, but was not associated with parasitaemia. The Pv-MAL patients showed increases in the mean platelet volume (MPV), which may be consistent with larger or megaplatelets. Contrary to the findings regarding the endemic control group, MPV and platelet distribution width (PDW) did not show an inverse correlation, due the increase in the heterogeneity of platelet width. In addition, the Pv-MAL patients presented increased IL-1β and reduced IL-12p70 and IL-2 serum concentrations. Furthermore, the reduction of these cytokines was associated with PDW values. MAIN CONCLUSIONS Our data demonstrate that an increase in MPV and the association between reductions of IL-2 and IL-12 and PDW values may be an immune response to thrombocytopenia in uncomplicated P. vivax malaria.
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Affiliation(s)
- Allyson Guimarães Costa
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Instituto de Pesquisa Clínica Carlos Borborema, Manaus, AM, Brasil.,Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Diretoria de Ensino e Pesquisa, Manaus, AM, Brasil.,Universidade do Estado do Amazonas, Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Manaus, AM, Brasil.,Universidade Federal do Amazonas, Programa de Pós-Graduação em Imunologia Básica e Aplicada, Manaus, AM, Brasil
| | - Yury Oliveira Chaves
- Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas e Maria Deane, Programa de Pós-Graduação em Biologia da Relação Patógeno-Hospedeiro, Manaus, AM, Brasil.,Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Programa de Pós-Graduação em Biologia Parasitária, Rio de Janeiro, RJ, Brasil
| | - Andréa Teixeira-Carvalho
- Fundação Oswaldo Cruz-Fiocruz, Centro de Pesquisas René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
| | - Rajendranath Ramasawmy
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Instituto de Pesquisa Clínica Carlos Borborema, Manaus, AM, Brasil.,Universidade Federal do Amazonas, Programa de Pós-Graduação em Imunologia Básica e Aplicada, Manaus, AM, Brasil.,Universidade Nilton Lins, Faculdade de Medicina, Manaus, AM, Brasil
| | - Lis Ribeiro Valle Antonelli
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Belo Horizonte, MG, Brasil
| | - Lucas Barbosa
- Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas e Maria Deane, Programa de Pós-Graduação em Biologia da Relação Patógeno-Hospedeiro, Manaus, AM, Brasil
| | - Antonio Balieiro
- Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas e Maria Deane, Programa de Pós-Graduação em Biologia da Relação Patógeno-Hospedeiro, Manaus, AM, Brasil
| | - Wuelton Marcelo Monteiro
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Instituto de Pesquisa Clínica Carlos Borborema, Manaus, AM, Brasil
| | - Maria Paula Mourão
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Instituto de Pesquisa Clínica Carlos Borborema, Manaus, AM, Brasil
| | - Marcus Vinicius Guimarães Lacerda
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Instituto de Pesquisa Clínica Carlos Borborema, Manaus, AM, Brasil.,Universidade do Estado do Amazonas, Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Manaus, AM, Brasil.,Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas e Maria Deane, Programa de Pós-Graduação em Biologia da Relação Patógeno-Hospedeiro, Manaus, AM, Brasil
| | - Olindo Assis Martins-Filho
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Diretoria de Ensino e Pesquisa, Manaus, AM, Brasil.,Fundação Oswaldo Cruz-Fiocruz, Centro de Pesquisas René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
| | | | - Adriana Malheiro
- Universidade do Estado do Amazonas, Programa de Pós-Graduação em Medicina Tropical, Manaus, AM, Brasil.,Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Diretoria de Ensino e Pesquisa, Manaus, AM, Brasil.,Universidade do Estado do Amazonas, Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Manaus, AM, Brasil.,Universidade Federal do Amazonas, Programa de Pós-Graduação em Imunologia Básica e Aplicada, Manaus, AM, Brasil
| | - Paulo Afonso Nogueira
- Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas e Maria Deane, Programa de Pós-Graduação em Biologia da Relação Patógeno-Hospedeiro, Manaus, AM, Brasil
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17
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Nallandhighal S, Park GS, Ho YY, Opoka RO, John CC, Tran TM. Whole-Blood Transcriptional Signatures Composed of Erythropoietic and NRF2-Regulated Genes Differ Between Cerebral Malaria and Severe Malarial Anemia. J Infect Dis 2019; 219:154-164. [PMID: 30060095 DOI: 10.1093/infdis/jiy468] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 07/24/2018] [Indexed: 02/03/2023] Open
Abstract
Background Among the severe malaria syndromes, severe malarial anemia (SMA) is the most common, whereas cerebral malaria (CM) is the most lethal. However, the mechanisms that lead to CM and SMA are unclear. Methods We compared transcriptomic profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without Plasmodium falciparum infection (n = 12) and determined the relationships among gene expression, hematological indices, and relevant plasma biomarkers. Results Both CM and SMA demonstrated predominantly upregulated enrichment of dendritic cell activation, inflammatory/Toll-like receptor/chemokines, and monocyte modules, but downregulated enrichment of lymphocyte modules. Nuclear factor, erythroid 2 like 2 (Nrf2)-regulated genes were overexpressed in children with SMA relative to CM, with the highest expression in children with both SMA and sickle cell disease (HbSS), corresponding with elevated plasma heme oxygenase-1 in this group. Erythroid and reticulocyte-specific signatures were markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/interferon-regulatory factor 2 module expression and plasma interferon-inducible protein-10/CXCL10 negatively correlated with reticulocyte-specific signatures. Conclusions Compared with SMA, CM is associated with downregulation of Nrf2-related and erythropoiesis signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.
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Affiliation(s)
- Srinivas Nallandhighal
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis
| | - Gregory S Park
- Division of Global Pediatrics, Department of Pediatrics, University of Minnesota Medical School, Minneapolis
| | - Yen-Yi Ho
- Department of Statistics, College of Arts and Sciences, University of South Carolina, Columbia
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University, Kampala, Uganda
| | - Chandy C John
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis.,Division of Global Pediatrics, Department of Pediatrics, University of Minnesota Medical School, Minneapolis.,Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis
| | - Tuan M Tran
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis.,Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis
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18
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Sato Y, Ries S, Stenzel W, Fillatreau S, Matuschewski K. The Liver-Stage Plasmodium Infection Is a Critical Checkpoint for Development of Experimental Cerebral Malaria. Front Immunol 2019; 10:2554. [PMID: 31736970 PMCID: PMC6837997 DOI: 10.3389/fimmu.2019.02554] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 10/15/2019] [Indexed: 12/20/2022] Open
Abstract
Cerebral malaria is a life-threatening complication of malaria in humans, and the underlying pathogenic mechanisms are widely analyzed in a murine model of experimental cerebral malaria (ECM). Here, we show abrogation of ECM by hemocoel sporozoite-induced infection of a transgenic Plasmodium berghei line that overexpresses profilin, whereas these parasites remain fully virulent in transfusion-mediated blood infection. We, thus, demonstrate the importance of the clinically silent liver-stage infection for modulating the onset of ECM. Even though both parasites triggered comparable splenic immune cell expansion and accumulation of antigen-experienced CD8+ T cells in the brain, infection with transgenic sporozoites did not lead to cerebral vascular damages and suppressed the recruitment of overall lymphocyte populations. Strikingly, infection with the transgenic strain led to maintenance of CD115+Ly6C+ monocytes, which disappear in infected animals prone to ECM. An early induction of IL-10, IL-12p70, IL-6, and TNF at the time when parasites emerge from the liver might lead to a diminished induction of hepatic immunity. Collectively, our study reveals the essential role of early host interactions in the liver that may dampen the subsequent pro-inflammatory immune responses and influence the occurrence of ECM, highlighting a novel checkpoint in this fatal pathology.
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Affiliation(s)
- Yuko Sato
- Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.,Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Stefanie Ries
- Immune Regulation Research Group, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
| | - Werner Stenzel
- Department of Neuropathology, Charité - Universitätmedizin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Simon Fillatreau
- Immune Regulation Research Group, Deutsches Rheuma-Forschungszentrum, Berlin, Germany.,Department of Immunology, Infectiology and Haematology (I2H), Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,AP-HP, Hôpital Necker Enfants Malades, Paris, France
| | - Kai Matuschewski
- Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.,Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
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Kraisin S, Verhenne S, Pham TT, Martinod K, Tersteeg C, Vandeputte N, Deckmyn H, Vanhoorelbeke K, Van den Steen PE, De Meyer SF. von Willebrand factor in experimental malaria-associated acute respiratory distress syndrome. J Thromb Haemost 2019; 17:1372-1383. [PMID: 31099973 PMCID: PMC9906160 DOI: 10.1111/jth.14485] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 05/02/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lethal complication of severe malaria, characterized by marked pulmonary inflammation. Patient studies have suggested a link between von Willebrand factor (VWF) and malaria severity. OBJECTIVES To investigate the role of VWF in the pathogenesis of experimental MA-ARDS. METHODS Plasmodium berghei NK65-E (PbNK65) parasites were injected in Vwf+/+ and Vwf-/- mice. Pathological parameters were assessed following infection. RESULTS In accordance with patients with severe malaria, plasma VWF levels were increased and ADAMTS13 activity levels were reduced in experimental MA-ARDS. ADAMTS13- and plasmin-independent reductions of high molecular weight VWF multimers were observed at the end stage of disease. Thrombocytopenia was VWF-independent because it was observed in both Vwf+/+ and Vwf-/- mice. Interestingly, Vwf-/- mice had a shorter survival time compared with Vwf+/+ controls following PbNK65 infection. Lung edema could not explain this shortened survival because alveolar protein levels in Vwf-/- mice were approximately two times lower than in Vwf+/+ controls. Parasite load, on the other hand, was significantly increased in Vwf-/- mice compared with Vwf+/+ mice in both peripheral blood and lung tissue. In addition, anemia was only observed in PbNK65-infected Vwf-/- mice. Of note, Vwf-/- mice presented with two times more reticulocytes, a preferential target of the parasites. CONCLUSIONS This study suggests that parasite load together with malarial anemia, rather than alveolar leakage, might contribute to shortened survival in PbNK65-infected Vwf-/- mice. VWF deficiency is associated with early reticulocytosis following PbNK65 infection, which potentially explains the increase in parasite load.
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Affiliation(s)
- Sirima Kraisin
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Sebastien Verhenne
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Thao-Thy Pham
- Laboratory of Immunoparasitology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Kimberly Martinod
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Claudia Tersteeg
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Nele Vandeputte
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Hans Deckmyn
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Philippe E Van den Steen
- Laboratory of Immunoparasitology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Simon F De Meyer
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
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Association between Inflammatory Cytokine Levels and Thrombocytopenia during Plasmodium falciparum and P. vivax Infections in South-Western Coastal Region of India. Malar Res Treat 2019; 2019:4296523. [PMID: 31110658 PMCID: PMC6487116 DOI: 10.1155/2019/4296523] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/11/2019] [Accepted: 03/26/2019] [Indexed: 12/20/2022] Open
Abstract
Background Thrombocytopenia is a most commonly observed complication during malaria infections. Inflammatory cytokines such as IL-1, IL-6, and IL-10 have been documented in malaria induced thrombocytopaenia. This study was aimed to understand the possible relationship between inflammatory cytokines across varying degrees of thrombocytopenia during P. vivax, P. falciparum, and mixed infections. Methods A hospital-based cross sectional study was conducted at District Wenlock Hospital in Mangaluru, a city situated along the south-western coastal region of Arabian Sea in India. In this study, blood samples from 627 malaria patients were analyzed for infected parasite species, clinical conditions, platelet levels, and key cytokines that are produced in response to infection; samples from 176 uninfected healthy individuals were used as controls. Results The results of our study showed a high prevalence of malarial thrombocytopenia (platelets <150 ×103/μl) in this endemic settings. About 62.7% patients had mild-to-moderate levels of thrombocytopenia and 16% patients had severe thrombocytopenia (platelets <50 × 103/μl). Upon comparison of cytokines across varying degrees of thrombocytopenia, irrespective of infecting species, the levels of TNF-α and IL-10 were significantly higher during thrombocytopenia, whereas IL-6 levels were considerably lower in severe thrombocytopenia patients suffering from P. vivax or P. falciparum infections. The severe clinical complications observed in patients with malarial thrombocytopenia included severe anemia (17.5%), acute renal failure (12.7%), jaundice (27.0%), metabolic acidosis (36.5%), spontaneous bleeding (3.2%), hypoglycemia (25.4%), hyperparasitemia (4.8%), acute respiratory distress syndrome (1.6%), pulmonary edema (19.0%), and cerebral malaria (1.6%) in various combinations. Conclusion Overall, the results of our study suggest that inflammatory cytokines influence the transformation of mild forms of thrombocytopenia into severe forms during malarial infections. Further studies are needed to understand the association of inflammatory cytokine responses with severe malaria complications and thrombocytopenia.
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Gupta P, Guddattu V, Saravu K. Characterization of platelet count and platelet indices and their potential role to predict severity in malaria. Pathog Glob Health 2019; 113:86-93. [PMID: 30967102 DOI: 10.1080/20477724.2019.1600855] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The association of hematological parameters especially platelet parameters with disease severity in malaria is poorly understood. We aimed to characterize the platelet parameters across Plasmodium falciparum and Plasmodium vivax malaria stratified by severity and to elucidate the potential role of platelet parameters to predict disease severity. Individuals > 18 years, of either gender with microscopically proven symptomatic malaria were prospectively enrolled between October 2014 and August 2016 in a tertiary center in Manipal, India. Severity of malaria was defined as per the WHO definition. Among 159 patients, 32 (20.1%) had severe malaria. 116 (73%) had infection with P. vivax, 37 (23%) P. falciparum and 6 mixed infection. Thrombocytopenia was seen in 32 (86.4%) of P. falciparum and 105 (90.5%) of P. vivax malaria cases. Patients with renal failure (p=0.02), shock (p=0.04) and liver dysfunction (p<0.001) had significantly lower platelet count compared to those who did not. Admission platelet count of 50,000 cell/mm3 had a sensitivity and specificity of 65.6% and 70.6% respectively, to discriminate severe malaria. A plateletcrit of 0.05% had a sensitivity and specificity of 65.6 % and of 70.6% respectively. Thrombocytopenia was seen in 89.3% of malaria cases due to both P. vivax and P. falciparum. Platelet count and plateletcrit could be used as markers of disease severity. P. vivax malaria which has been traditionally regarded as 'benign' can be as sinister and menacing as P. falciparum malaria and hence warrants equal attention. Unnecessary transfusion of platelets should be avoided.
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Affiliation(s)
- Pranjal Gupta
- a Department of Internal Medicine , Kasturba Medical College, Manipal Academy of Higher Education , Manipal , India
| | - Vasudev Guddattu
- b Department of Statistics , Prasanna School of Public Health, Manipal Academy of Higher Education , Manipal , Karnataka , India
| | - Kavitha Saravu
- a Department of Internal Medicine , Kasturba Medical College, Manipal Academy of Higher Education , Manipal , India.,c Manipal McGill Center for Infectious Diseases , Prasanna School of Public Health, Manipal Academy of Higher Education , Manipal , Karnataka , India
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22
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Kho S, Barber BE, Johar E, Andries B, Poespoprodjo JR, Kenangalem E, Piera KA, Ehmann A, Price RN, William T, Woodberry T, Foote S, Minigo G, Yeo TW, Grigg MJ, Anstey NM, McMorran BJ. Platelets kill circulating parasites of all major Plasmodium species in human malaria. Blood 2018; 132:1332-1344. [PMID: 30026183 PMCID: PMC6161646 DOI: 10.1182/blood-2018-05-849307] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/27/2018] [Indexed: 01/12/2023] Open
Abstract
Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet-erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet-erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.
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Affiliation(s)
- Steven Kho
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
| | - Bridget E Barber
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
| | - Edison Johar
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Benediktus Andries
- Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
| | - Jeanne R Poespoprodjo
- Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
- Rumah Sakit Umum Daerah Kabupaten Mimika, Timika, Papua, Indonesia
- Department of Paediatrics, University of Gadjah Mada, Yogyakarta, Indonesia
| | - Enny Kenangalem
- Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
- Rumah Sakit Umum Daerah Kabupaten Mimika, Timika, Papua, Indonesia
| | - Kim A Piera
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
| | - Anna Ehmann
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Ric N Price
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
| | - Timothy William
- Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
- Jesselton Medical Centre, Kota Kinabalu, Sabah, Malaysia; and
- Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Ministry of Health, Malaysia
| | - Tonia Woodberry
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
| | - Simon Foote
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Gabriela Minigo
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
| | - Tsin W Yeo
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
| | - Matthew J Grigg
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
| | - Nicholas M Anstey
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
| | - Brendan J McMorran
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
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The Glycosylphosphatidylinositol Transamidase Complex Subunit PbGPI16 of Plasmodium berghei Is Important for Inducing Experimental Cerebral Malaria. Infect Immun 2018; 86:IAI.00929-17. [PMID: 29784863 DOI: 10.1128/iai.00929-17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/18/2018] [Indexed: 02/07/2023] Open
Abstract
In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 (Δpbgpi16) in the rodent malaria parasite Plasmodium berghei strain ANKA led to a significant reduction of the amounts of GPIs in the membranes of merozoites, as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, Δpbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 mutant-infected mice displayed much less severe brain pathology, and considerably fewer Δpbgpi16 mutant-infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria.
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24
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Moussa E, Huang H, Ahras M, Lall A, Thezenas ML, Fischer R, Kessler BM, Pain A, Billker O, Casals-Pascual C. Proteomic profiling of the brain of mice with experimental cerebral malaria. J Proteomics 2018; 180:61-69. [DOI: 10.1016/j.jprot.2017.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 05/15/2017] [Accepted: 06/02/2017] [Indexed: 11/24/2022]
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Hematological Parameters and Hemozoin-Containing Leukocytes and Their Association with Disease Severity among Malaria Infected Children: A Cross-Sectional Study at Pawe General Hospital, Northwest Ethiopia. Interdiscip Perspect Infect Dis 2017; 2017:8965729. [PMID: 28298924 PMCID: PMC5337349 DOI: 10.1155/2017/8965729] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 01/19/2017] [Accepted: 01/26/2017] [Indexed: 11/21/2022] Open
Abstract
Hematological parameter changes are the most common complications in malaria. We aimed to determine the hematological parameters and hemozoin-containing leukocytes and their association with disease severity in malaria infected children aged between 1 and 15 years. A facility-based cross-sectional study was conducted at Pawe General Hospital from July 31 to December 30, 2014. Demographic and clinical data were collected using structured questionnaire. Blood specimen was collected from each study participant for hematological investigations. Data were analyzed using SPSS version 20. The overall prevalence of anemia was 40.3%, most of which were mildly anemic. Leukocytosis was found in 15.4% of study participants. More than a fourth (27%) of the children had severe malaria. Hemozoin-containing monocytes and neutrophils were found in 80.1% and 58.9% of the study participants, respectively. Under-five years of age (AOR = 3.01, 95% CI: 1.83–7.39, P < 0.001), leukocytosis (AOR = 3.20, 95% CI: 1.65–6.24, P = 0.001), mean hemozoin-containing monocytes >5% (AOR = 6.26, 95% CI: 2.14–14.29, P < 0.001), mean hemozoin-containing neutrophils >5% (AOR = 7.93, 95% CI: 3.09–16.86, P < 0.001), and high density parasitemia (AOR = 1.90, 95% CI: 1.13–3.18, P = 0.015) were associated with severe malaria. Hemozoin-containing leukocytes, leukocytosis, and other identified associated factors should be considered for proper management of children with severe malaria.
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Fougère A, Jackson AP, Paraskevi Bechtsi D, Braks JAM, Annoura T, Fonager J, Spaccapelo R, Ramesar J, Chevalley-Maurel S, Klop O, van der Laan AMA, Tanke HJ, Kocken CHM, Pasini EM, Khan SM, Böhme U, van Ooij C, Otto TD, Janse CJ, Franke-Fayard B. Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole. PLoS Pathog 2016; 12:e1005917. [PMID: 27851824 PMCID: PMC5113031 DOI: 10.1371/journal.ppat.1005917] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 09/06/2016] [Indexed: 01/05/2023] Open
Abstract
Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC). P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC) and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP) we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START) domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host) phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites. Malaria-parasites invade and multiply in hepatocytes and erythrocytes. The human parasite P. falciparum transports proteins encoded by multigene families onto the surface of erythrocytes, mediating interactions between infected red blood cells (iRBCs) and other host-cells and are thought to play a key role in parasite survival during blood-stage development. The function of other exported Plasmodium protein families remains largely unknown. We provide novel insights into expression and cellular location of proteins encoded by three large multigene families of rodent malaria parasites (Fam-a, Fam-b and PIR). Multiple members of the same family are expressed in a single iRBC, unlike P. falciparum PfEMP1 proteins where individual iRBCs express only a single member. Most proteins we examined are located in the RBC cytoplasm and are not transported onto the iRBC surface membrane, indicating that these proteins are unlikely to mediate interactions between iRBCs and host-cells. Unexpectedly, liver stages also express many of these proteins, where they locate to the vacuole surrounding the parasite inside the hepatocyte. In support of a role of these proteins for parasite growth within their host cells we provide evidence that Fam-A proteins have a role in uptake and transport of (host) phosphatidylcholine for parasite-membrane synthesis.
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Affiliation(s)
- Aurélie Fougère
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Experimental Medicine, University of Perugia, Italy
| | - Andrew P. Jackson
- Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UnitedKingdom
| | | | - Joanna A. M. Braks
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Takeshi Annoura
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Department of Parasitology, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Jannik Fonager
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Microbiological Diagnostics and Virology, Statens Serum Institute, Copenhagen, Denmark
| | | | - Jai Ramesar
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Séverine Chevalley-Maurel
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Onny Klop
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands
| | | | - Hans J. Tanke
- Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | | | - Erica M. Pasini
- Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands
| | - Shahid M. Khan
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Ulrike Böhme
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UnitedKingdom
| | - Christiaan van Ooij
- The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, UnitedKingdom
| | - Thomas D. Otto
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UnitedKingdom
| | - Chris J. Janse
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Blandine Franke-Fayard
- Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- * E-mail:
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Middleton EA, Weyrich AS, Zimmerman GA. Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases. Physiol Rev 2016; 96:1211-59. [PMID: 27489307 PMCID: PMC6345245 DOI: 10.1152/physrev.00038.2015] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury.
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Affiliation(s)
- Elizabeth A Middleton
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and the Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Andrew S Weyrich
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and the Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Guy A Zimmerman
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and the Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
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Scherer EF, Cantarini DG, Siqueira R, Ribeiro EB, Braga ÉM, Honório-França AC, França EL. Cytokine modulation of human blood viscosity from vivax malaria patients. Acta Trop 2016; 158:139-147. [PMID: 26948901 DOI: 10.1016/j.actatropica.2016.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 02/29/2016] [Accepted: 03/01/2016] [Indexed: 11/28/2022]
Abstract
Malaria is a major infectious disease in several countries and is caused by protozoa of the genus Plasmodium. In vivax malaria patients, inflammatory processes occur, as well as changes in cytokines and blood flow. The present study analyzed the cytokine modulation of blood viscosity from patients infected with Plasmodium vivax (P. vivax). Blood samples were collected from 42 non-infected individuals (control group) and 37 individuals infected with P. vivax. The IL-2, IL-4, IL-6, IL-10, TNFα, TGF-β and IL-17 cytokine concentrations in the serum were assessed, and the blood rheological properties were determined. The analysis of blood viscosity for shear rates revealed that the blood viscosity of the infected patients was significantly greater than that of the non-infected individuals. The viscosity of the blood was greater in the infected individuals than in the non-infected subjects. The serum from individuals with P. vivax infections exhibited higher IFN-γ and IL-17 concentrations and lower TGF-β levels. Incubation of the blood from infected individuals with IL-17 or IL-17 associated with IFN-γ reduced the viscosity to rates equivalent to the blood from non-infected individuals. Independently of cytokine modulation, no correlation was found between the parasitemia and blood viscosity of the infected patients. These data suggest that the alterations of blood viscosity are relevant as an auxiliary tool for the clinical diagnosis of disease. In malaria, erythrocytes are more sensitive to osmotic shock, and the reduction of viscosity by IL-17 may be related to a possible immunomodulator agent during infection.
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Affiliation(s)
- Edson Fredulin Scherer
- Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Déborah Giovanna Cantarini
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
| | - Renan Siqueira
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
| | - Elton Brito Ribeiro
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - Érika Martins Braga
- Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | | | - Eduardo Luzía França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
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Emerging roles for hemostatic dysfunction in malaria pathogenesis. Blood 2016; 127:2281-8. [PMID: 26851291 DOI: 10.1182/blood-2015-11-636464] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 01/27/2016] [Indexed: 11/20/2022] Open
Abstract
Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.
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Depletion of Phagocytic Cells during Nonlethal Plasmodium yoelii Infection Causes Severe Malaria Characterized by Acute Renal Failure in Mice. Infect Immun 2016; 84:845-55. [PMID: 26755155 DOI: 10.1128/iai.01005-15] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 01/04/2016] [Indexed: 11/20/2022] Open
Abstract
In the current study, we examined the effects of depletion of phagocytes on the progression of Plasmodium yoelii 17XNL infection in mice. Strikingly, the depletion of phagocytic cells, including macrophages, with clodronate in the acute phase of infection significantly reduced peripheral parasitemia but increased mortality. Moribund mice displayed severe pathological damage, including coagulative necrosis in liver and thrombi in the glomeruli, fibrin deposition, and tubular necrosis in kidney. The severity of infection was coincident with the increased sequestration of parasitized erythrocytes, the systematic upregulation of inflammation and coagulation, and the disruption of endothelial integrity in the liver and kidney. Aspirin was administered to the mice to minimize the risk of excessive activation of the coagulation response and fibrin deposition in the renal tissue. Interestingly, treatment with aspirin reduced the parasite burden and pathological lesions in the renal tissue and improved survival of phagocyte-depleted mice. Our data imply that the depletion of phagocytic cells, including macrophages, in the acute phase of infection increases the severity of malarial infection, typified by multiorgan failure and high mortality.
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A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. Blood 2015; 127:1192-201. [PMID: 26511133 DOI: 10.1182/blood-2015-07-654921] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/19/2015] [Indexed: 01/28/2023] Open
Abstract
Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF(-/-) C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF(-/-) mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF(-/-) and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood-brain barrier permeability was significantly attenuated in VWF(-/-) mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.
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Ketema T, Bacha K, Alemayehu E, Ambelu A. Incidence of Severe Malaria Syndromes and Status of Immune Responses among Khat Chewer Malaria Patients in Ethiopia. PLoS One 2015; 10:e0131212. [PMID: 26173100 PMCID: PMC4501669 DOI: 10.1371/journal.pone.0131212] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 05/30/2015] [Indexed: 12/22/2022] Open
Abstract
Although more emphasis has been given to the genetic and environmental factors that determine host vulnerability to malaria, other factors that might have a crucial role in burdening the disease have not been evaluated yet. Therefore, this study was designed to assess the effect of khat chewing on the incidence of severe malaria syndromes and immune responses during malaria infection in an area where the two problems co-exist. Clinical, physical, demographic, hematological, biochemical and immunological data were collected from Plasmodium falciparum mono-infected malaria patients (age ≥ 10 years) seeking medication in Halaba Kulito and Jimma Health Centers. In addition, incidences of severe malaria symptoms were assessed. The data were analyzed using SPSS (version 20) software. Prevalence of current khat chewer malaria patients was 57.38% (95%CI =53-61.56%). Malaria symptoms such as hyperpyrexia, prostration and hyperparasitemia were significantly lower (P<0.05) among khat chewer malaria patients. However, relative risk to jaundice and renal failure were significantly higher (P<0.05) in khat chewers than in non-khat chewer malaria patients. Longer duration of khat use was positively associated with incidence of anemia. IgM and IgG antibody titers were significantly higher (P<0.05) among khat chewer malaria patients than among malaria positive non-chewers. Although levels of IgG subclasses in malaria patients did not show significant differences (P>0.05), IgG3 antibody was significantly higher (P<0.001) among khat chewer malaria patients. Moreover, IgM, IgG, IgG1and IgG3 antibodies had significant negative association (P<0.001) with parasite burden and clinical manifestations of severe malaria symptoms, but not with severe anemia and hypoglycemia. Additionally, a significant increment (P<0.05) in CD4+ T-lymphocyte population was observed among khat users. Khat might be an important risk factor for incidence of some severe malaria complications. Nevertheless, it can enhance induction of humoral immune response and CD4+ T-lymphocyte population during malaria infection. This calls for further investigation on the effect of khat on parasite or antigen-specifc protective malaria immunity and analysis of cytokines released upon malaria infection among khat chewers.
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Affiliation(s)
- Tsige Ketema
- Department of Environmental Health Sciences and Technology, College of Health Sciences, Jimma University, Jimma, Ethiopia
- Department of Biology,College of Natural Sciences, Jimma University, Jimma, Ethiopia
- * E-mail:
| | - Ketema Bacha
- Department of Biology,College of Natural Sciences, Jimma University, Jimma, Ethiopia
| | - Esayas Alemayehu
- School of Civil and Environmental Engineering, Institute of Technology, Jimma University, Jimma, Ethiopia
| | - Argaw Ambelu
- Department of Environmental Health Sciences and Technology, College of Health Sciences, Jimma University, Jimma, Ethiopia
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Abstract
While the interactions between Gram-positive bacteria and platelets have been well characterized, there is a paucity of data on the interaction between other pathogens and platelets. However, thrombocytopenia is a common feature with many infections especially viral hemorrhagic fever. The little available data on these interactions indicate a similarity with bacteria-platelet interactions with receptors such as FcγRIIa and Toll-Like Receptors (TLR) playing key roles with many pathogens. This review summarizes the known interactions between platelets and pathogens such as viruses, fungi and parasites.
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Affiliation(s)
- Ana Lopez Alonso
- Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland , Dublin , Ireland
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Ketema T, Yohannes M, Alemayehu E, Ambelu A. Effect of chronic khat (Catha edulis, Forsk) use on outcome of Plasmodium berghei ANKA infection in Swiss albino mice. BMC Infect Dis 2015; 15:170. [PMID: 25886020 PMCID: PMC4392739 DOI: 10.1186/s12879-015-0911-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/23/2015] [Indexed: 12/22/2022] Open
Abstract
Background The objective of this study was to explore effects of khat (Catha edulis) on outcome of rodent malaria infection and its anti-plasmodial activities on Plasmodium berghei ANKA (PbA). Methods Female Swiss albino mice were orally treated with crude khat (Catha edulis) extracts (100, 200 and 300 mg/kg) on a daily basis for 4 weeks prior to PbA infection. Physical, clinical, hematological, biochemical and histo-pathological features of the mice were assessed. In addition, in vivo anti-plasmodial activities of khat were evaluated. Results The finding of this study showed that khat use was strongly associated with increment of levels of liver and kidney biomarkers, leucopenia, severe anemia, rise in level of inflammation biomarkers: C-reactive protein (CRP), uric acid (UA), increased monocyte-lymphocyte count ratio (MLCR), manifestation of cerebral malaria symptoms such as ataxia, paralysis and deviation of the head but with no pulmonary edema. Significantly lower level of parasitemia (P < 0.05), rectal temperature, but, high level of hemoglobin were observed at the early stage of the PbA infection in khat treated mice than the control. With extension of the treatment period, however, drastic increments were observed in parasite load and rectal temperature although there was reduction in hemoglobin (Hb) level. Moreover, khat showed poor anti-plasmodial activity with <10% parasite suppression activity and lack protection against major malaria symptoms. The significant reduction (P < 0.01) of hematological parameters during PbA infection strengthen the notion that hematological parameters could be good predictors of severe malaria complications in human. Conclusions In mice model treated with khat prior to infection with the rodent malaria parasite, khat was found to worsen manifestation of most malaria complications. Furthermore, the same plant showed poor in vivo anti-plasmodial activity and protection against major malaria symptoms.
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Affiliation(s)
- Tsige Ketema
- Department of Environmental Health Sciences and Technology, College of Health Sciences, Jimma University, Jimma, Ethiopia. .,Department of Biology, College of Natural Sciences, Jimma University, Jimma, Ethiopia.
| | - Moti Yohannes
- Department of Microbiology and Veterinary Public Health, College of Agriculture and Veterinary Medicine, Jimma University, Jimma, Ethiopia.
| | - Esayas Alemayehu
- School of Civil and Environmental Engineering, Jimma University Institute of Technology, Jimma, Ethiopia.
| | - Argaw Ambelu
- Department of Environmental Health Sciences and Technology, College of Health Sciences, Jimma University, Jimma, Ethiopia.
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35
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McFadyen JD, Kaplan ZS. Platelets Are Not Just for Clots. Transfus Med Rev 2015; 29:110-9. [DOI: 10.1016/j.tmrv.2014.11.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 11/04/2014] [Accepted: 11/09/2014] [Indexed: 12/18/2022]
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Nacer A, Movila A, Sohet F, Girgis NM, Gundra UM, Loke P, Daneman R, Frevert U. Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. PLoS Pathog 2014; 10:e1004528. [PMID: 25474413 PMCID: PMC4256476 DOI: 10.1371/journal.ppat.1004528] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 10/17/2014] [Indexed: 12/16/2022] Open
Abstract
Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.
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Affiliation(s)
- Adéla Nacer
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
| | - Alexandru Movila
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
| | - Fabien Sohet
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
| | - Natasha M. Girgis
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
| | - Uma Mahesh Gundra
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
| | - P'ng Loke
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
| | - Richard Daneman
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
| | - Ute Frevert
- Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America
- * E-mail:
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Monteiro MC, Oliveira FR, Oliveira GB, Romao PRT, Maia CSF. Neurological and behavioral manifestations of cerebral malaria: An update. World J Transl Med 2014; 3:9-16. [DOI: 10.5528/wjtm.v3.i1.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 02/28/2014] [Accepted: 03/14/2014] [Indexed: 02/05/2023] Open
Abstract
Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the physiological changes they induce in their hosts. Malaria is a disease caused by Plasmodium sp. that in its cerebral form may lead to acute or long-term neurological deficits, even with effective antimalarial therapy, causing vascular obstruction, reduced cerebral blood flow and many other changes. However, Plasmodium falciparum infection can also develop into a cerebral malaria (CM) disease that can produce neurological damage. This review will discuss the mechanisms involved in the neuropathology caused by CM, focusing on alterations in cognitive, behavior and neurological functions in human and experimental models.
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Thachil J, Owusu-Ofori S, Bates I. Haematological Diseases in the Tropics. MANSON'S TROPICAL INFECTIOUS DISEASES 2014. [PMCID: PMC7167525 DOI: 10.1016/b978-0-7020-5101-2.00066-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Speth C, Löffler J, Krappmann S, Lass-Flörl C, Rambach G. Platelets as immune cells in infectious diseases. Future Microbiol 2013; 8:1431-51. [DOI: 10.2217/fmb.13.104] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Platelets have been shown to cover a broad range of functions. Besides their role in hemostasis, they have immunological functions and thus participate in the interaction between pathogens and host defense. Platelets have a broad repertoire of receptor molecules that enable them to sense invading pathogens and infection-induced inflammation. Consequently, platelets exert antimicrobial effector mechanisms, but also initiate an intense crosstalk with other arms of the innate and adaptive immunity, including neutrophils, monocytes/macrophages, dendritic cells, B cells and T cells. There is a fragile balance between beneficial antimicrobial effects and detrimental reactions that contribute to the pathogenesis, and many pathogens have developed mechanisms to influence these two outcomes. This review aims to highlight aspects of the interaction strategies between platelets and pathogenic bacteria, viruses, fungi and parasites, in addition to the subsequent networking between platelets and other immune cells, and the relevance of these processes for the pathogenesis of infections.
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Affiliation(s)
- Cornelia Speth
- Division of Hygiene & Medical Microbiology, Innsbruck Medical University Fritz-Pregl-Straße 3, A-6020 Innsbruck, Austria
| | - Jürgen Löffler
- Laboratory of Innate Immunity, Infection, Inflammation, University Hospital Würzburg, Würzburg, Germany
| | - Sven Krappmann
- Microbiology Institute – Clinical Microbiology, Immunology & Hygiene, University Hospital of Erlangen & Friedrich-Alexander-University Erlangen-Nürnberg, Germany
| | - Cornelia Lass-Flörl
- Division of Hygiene & Medical Microbiology, Innsbruck Medical University Fritz-Pregl-Straße 3, A-6020 Innsbruck, Austria
| | - Günter Rambach
- Division of Hygiene & Medical Microbiology, Innsbruck Medical University Fritz-Pregl-Straße 3, A-6020 Innsbruck, Austria
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Palomo J, Fauconnier M, Coquard L, Gilles M, Meme S, Szeremeta F, Fick L, Franetich JF, Jacobs M, Togbe D, Beloeil JC, Mazier D, Ryffel B, Quesniaux VF. Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stagePlasmodium bergheiANKA. Eur J Immunol 2013; 43:2683-95. [DOI: 10.1002/eji.201343327] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 03/01/2013] [Accepted: 04/25/2013] [Indexed: 11/11/2022]
Affiliation(s)
- Jennifer Palomo
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
| | - Mathilde Fauconnier
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
| | - Laurie Coquard
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
| | - Maïlys Gilles
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
| | - Sandra Meme
- CNRS, Centre de Biophysique Moléculaire; Orléans France
| | | | - Lizette Fick
- Institute of Infectious Disease and Molecular Medicine; Cape Town South Africa
| | - Jean-François Franetich
- Université Pierre et Marie Curie-Paris 6, UMR S945; Paris France
- Institut National de la Santé et de la Recherche Médicale U945; Paris France
- Groupe Hospitalier Pitié-Salpêtrière Service Parasitologie-Mycologie; Paris France
| | - Muazzam Jacobs
- Institute of Infectious Disease and Molecular Medicine; Cape Town South Africa
| | | | | | - Dominique Mazier
- Université Pierre et Marie Curie-Paris 6, UMR S945; Paris France
- Institut National de la Santé et de la Recherche Médicale U945; Paris France
- Groupe Hospitalier Pitié-Salpêtrière Service Parasitologie-Mycologie; Paris France
| | - Bernhard Ryffel
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
- Institute of Infectious Disease and Molecular Medicine; Cape Town South Africa
| | - Valerie F.J. Quesniaux
- CNRS, UMR7355; Orléans France
- Experimental and Molecular Immunology and Neurogenetics; University of Orleans; Orléans France
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Coelho HCC, Lopes SCP, Pimentel JPD, Nogueira PA, Costa FTM, Siqueira AM, Melo GC, Monteiro WM, Malheiro A, Lacerda MVG. Thrombocytopenia in Plasmodium vivax malaria is related to platelets phagocytosis. PLoS One 2013; 8:e63410. [PMID: 23723981 PMCID: PMC3665752 DOI: 10.1371/journal.pone.0063410] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 04/02/2013] [Indexed: 12/15/2022] Open
Abstract
Background Although thrombocytopenia is a hematological disorder commonly reported in malarial patients, its mechanisms are still poorly understood, with only a few studies focusing on the role of platelets phagocytosis. Methods and Findings Thirty-five malaria vivax patients and eight healthy volunteers (HV) were enrolled in the study. Among vivax malaria patients, thrombocytopenia (<150,000 platelets/µL) was found in 62.9% (22/35). Mean platelet volume (MPV) was higher in thrombocytopenic patients as compared to non- thrombocytopenic patients (p = 0.017) and a negative correlation was found between platelet count and MPV (r = −0.483; p = 0.003). Platelets from HV or patients were labeled with 5-chloromethyl fluorescein diacetate (CMFDA), incubated with human monocytic cell line (THP-1) and platelet phagocytosis index was analyzed by flow cytometry. The phagocytosis index was higher in thrombocytopenic patients compared to non-thrombocytopenic patients (p = 0.042) and HV (p = 0.048). A negative correlation was observed between platelet count and phagocytosis index (r = −0.402; p = 0.016). Platelet activation was assessed measuring the expression of P-selectin (CD62-P) in platelets’ surface by flow cytometry. No significant difference was found in the expression of P-selectin between thrombocytopenic patients and HV (p = 0.092). After evaluating the cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17) in the patients’ sera, levels of IL-6, IL-10 and IFN-γ were elevated in malaria patients compared to HV. Moreover, IL-6 and IL-10 values were higher in thrombocytopenic patients than non-thrombocytopenic ones (p = 0.044 and p = 0.017, respectively. In contrast, TNF-α levels were not different between the three groups, but a positive correlation was found between TNF-α and phagocytosis index (r = −0.305; p = 0.037). Conclusion/Significance Collectively, our findings indicate that platelet phagocytosis may contribute to thrombocytopenia found in vivax malaria. Finally, we believe that this study opens new avenues to explore the mechanisms involved in platelet dysfunction, commonly found in vivax malaria patients.
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Affiliation(s)
- Helena Cristina C. Coelho
- Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil
| | | | - João Paulo D. Pimentel
- Instituto Leônidas e Maria Deane, Fiocruz, Manaus, Amazonas, Brazil
- Fundação de Hematologia e Hemoterapia do Amazonas, Manaus, Amazonas, Brazil
| | | | | | - André M. Siqueira
- Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil
| | - Gisely C. Melo
- Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
| | - Wuelton M. Monteiro
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil
- Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
| | - Adriana Malheiro
- Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
- Fundação de Hematologia e Hemoterapia do Amazonas, Manaus, Amazonas, Brazil
| | - Marcus V. G. Lacerda
- Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil
- * E-mail:
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Wilson NO, Solomon W, Anderson L, Patrickson J, Pitts S, Bond V, Liu M, Stiles JK. Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria. PLoS One 2013; 8:e60898. [PMID: 23630573 PMCID: PMC3618178 DOI: 10.1371/journal.pone.0060898] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 03/04/2013] [Indexed: 02/05/2023] Open
Abstract
Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients.
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Affiliation(s)
- Nana O. Wilson
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Wesley Solomon
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Leonard Anderson
- Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - John Patrickson
- Department of Pathology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Sidney Pitts
- Department of Pathology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Vincent Bond
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Mingli Liu
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Jonathan K. Stiles
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
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DellaValle B, Staalsoe T, Kurtzhals JAL, Hempel C. Investigation of hydrogen sulfide gas as a treatment against P. falciparum, murine cerebral malaria, and the importance of thiolation state in the development of cerebral malaria. PLoS One 2013; 8:e59271. [PMID: 23555646 PMCID: PMC3608628 DOI: 10.1371/journal.pone.0059271] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 02/12/2013] [Indexed: 01/16/2023] Open
Abstract
Introduction Cerebral malaria (CM) is a potentially fatal cerebrovascular disease of complex pathogenesis caused by Plasmodium falciparum. Hydrogen sulfide (HS) is a physiological gas, similar to nitric oxide and carbon monoxide, involved in cellular metabolism, vascular tension, inflammation, and cell death. HS treatment has shown promising results as a therapy for cardio- and neuro- pathology. This study investigates the effects of fast (NaHS) and slow (GYY4137) HS-releasing drugs on the growth and metabolism of P. falciparum and the development of P. berghei ANKA CM. Moreover, we investigate the role of free plasma thiols and cell surface thiols in the pathogenesis of CM. Methods P. falciparum was cultured in vitro with varying doses of HS releasing drugs compared with artesunate. Growth and metabolism were quantified. C57Bl/6 mice were infected with P. berghei ANKA and were treated with varying doses and regimes of HS-releasing drugs. Free plasma thiols and cell surface thiols were quantified in CM mice and age-matched healthy controls. Results HS-releasing drugs significantly and dose-dependently inhibited P. falciparum growth and metabolism. Treatment of CM did not affect P. berghei growth, or development of CM. Interestingly, CM was associated with lower free plasma thiols, reduced leukocyte+erythrocyte cell surface thiols (infection day 3), and markedly (5-fold) increased platelet cell surface thiols (infection day 7). Conclusions HS inhibits P. falciparum growth and metabolism in vitro. Reduction in free plasma thiols, cell surface thiols and a marked increase in platelet cell surface thiols are associated with development of CM. HS drugs were not effective in vivo against murine CM.
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Affiliation(s)
- Brian DellaValle
- Centre for Medical Parasitology, Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark.
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de Macchi BM, Miranda FJB, de Souza FS, de Carvalho ECQ, Albernaz AP, do Nascimento JLM, DaMatta RA. Chickens treated with a nitric oxide inhibitor became more resistant to Plasmodium gallinaceum infection due to reduced anemia, thrombocytopenia and inflammation. Vet Res 2013; 44:8. [PMID: 23398940 PMCID: PMC3582474 DOI: 10.1186/1297-9716-44-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 02/05/2013] [Indexed: 02/04/2023] Open
Abstract
Malaria is a serious infectious disease caused by parasites of the Plasmodium genus that affect different vertebrate hosts. Severe malaria leads to host death and involves different pathophysiological phenomena such as anemia, thrombocytopenia and inflammation. Nitric oxide (NO) is an important effector molecule in this disease, but little is known about its role in avian malaria models. Plasmodium gallinaceum-infected chickens were treated with aminoguanidine (AG), an inhibitor of inducible nitric oxide synthase, to observe the role of NO in the pathogenesis of this avian model. AG increased the survival of chickens, but also induced higher parasitemia. Treated chickens demonstrated reduced anemia and thrombocytopenia. Moreover, erythrocytes at different stages of maturation, heterophils, monocytes and thrombocytes were infected by Plasmodium gallinaceum and animals presented a generalized leucopenia. Activated leukocytes and thrombocytes with elongated double nuclei were observed in chickens with higher parasitemia; however, eosinophils were not involved in the infection. AG reduced levels of hemozoin in the spleen and liver, indicating lower inflammation. Taken together, the results suggest that AG reduced anemia, thrombocytopenia and inflammation, explaining the greater survival rate of the treated chickens.
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Affiliation(s)
- Barbarella Matos de Macchi
- Laboratório de Biologia Celular e Tecidual, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense, 28013-602, Campos dos Goytacazes, RJ, Brazil.
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Cserti-Gazdewich CM, Dhabangi A, Musoke C, Ssewanyana I, Ddungu H, Nakiboneka-Ssenabulya D, Nabukeera-Barungi N, Mpimbaza A, Dzik WH. Inter-relationships of cardinal features and outcomes of symptomatic pediatric Plasmodium falciparum MALARIA in 1,933 children in Kampala, Uganda. Am J Trop Med Hyg 2013; 88:747-756. [PMID: 23358640 PMCID: PMC3617864 DOI: 10.4269/ajtmh.12-0668] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov).
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Affiliation(s)
| | | | | | | | | | | | | | | | - Walter H. Dzik
- *Address correspondence to Walter H. Dzik, Department of Pathology, Blood Transfusion Service, J224, Harvard University, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail:
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Ferroni P, Vazzana N, Riondino S, Cuccurullo C, Guadagni F, Davì G. Platelet function in health and disease: from molecular mechanisms, redox considerations to novel therapeutic opportunities. Antioxid Redox Signal 2012; 17:1447-85. [PMID: 22458931 DOI: 10.1089/ars.2011.4324] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Increased oxidative stress appears to be of fundamental importance in the pathogenesis and development of several disease processes. Indeed, it is well known that reactive oxygen species (ROS) exert critical regulatory functions within the vascular wall, and it is, therefore, plausible that platelets represent a relevant target for their action. Platelet activation cascade (including receptor-mediated tethering to the endothelium, rolling, firm adhesion, aggregation, and thrombus formation) is tightly regulated. In addition to already well-defined platelet regulatory factors, ROS may participate in the regulation of platelet activation. It is already established that enhanced ROS release from the vascular wall can indirectly affect platelet activity by scavenging nitric oxide (NO), thereby decreasing the antiplatelet properties of endothelium. On the other hand, recent data suggest that platelets themselves generate ROS, which may evoke pro-thrombotic responses, triggering many biological processes participating in atherosclerosis initiation, progression, and complication. That oxidative stress may alter platelet function is conceivable when considering that antioxidants play a role in the prevention of cardiovascular disease, although the precise mechanism accounting for changes attributable to antioxidants in atherosclerosis remains unknown. It is possible that the effects of antioxidants may be a consequence of their enhancing or promoting the antiplatelet effects of NO derived from both endothelial cells and platelets. This review focuses on current knowledge regarding ROS-dependent regulation of platelet function in health and disease, and summarizes in vitro and in vivo evidence for their physiological and potential therapeutic relevance.
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Affiliation(s)
- Patrizia Ferroni
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy
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Nacer A, Movila A, Baer K, Mikolajczak SA, Kappe SHI, Frevert U. Neuroimmunological blood brain barrier opening in experimental cerebral malaria. PLoS Pathog 2012; 8:e1002982. [PMID: 23133375 PMCID: PMC3486917 DOI: 10.1371/journal.ppat.1002982] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 09/07/2012] [Indexed: 12/31/2022] Open
Abstract
Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB. Plasmodium falciparum, the deadliest of all human malaria parasites, can cause cerebral malaria, a severe and frequently fatal complication of this devastating disease. Young children are predominantly at risk and may progress rapidly from the first signs of neurological involvement to coma and death. Here we used a murine model for high-resolution in vivo imaging to demonstrate that cerebral malaria, but not high parasitemia and severe anemia, is associated with extensive leakage of fluid from cerebral blood vessels into the brain tissue. This vascular leakage occurs downstream from the capillary bed, at the neuroimmunological blood brain barrier, a site recently recognized as the immune cell entry point into the brain during neuroinflammation. Vascular leakage is closely associated with the appearance of neurological signs suggesting that the ultimate cause of brain edema, coma and death in cerebral malaria is a widespread opening of the neuroimmunological blood brain barrier. Indeed, vascular leakage, neurological signs, and death from ECM can be prevented with endothelial barrier-stabilizing drugs. Based on the unique role of this anatomical feature in neuroinflammation, our findings are expected to have implications for other infectious diseases and autoimmune disorders of the central nervous system.
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Affiliation(s)
- Adela Nacer
- Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
| | - Alexandru Movila
- Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
| | - Kerstin Baer
- Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
| | | | - Stefan H. I. Kappe
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Ute Frevert
- Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
- * E-mail:
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Billig EMW, O'Meara WP, Riley EM, McKenzie FE. Developmental allometry and paediatric malaria. Malar J 2012; 11:64. [PMID: 22394452 PMCID: PMC3331816 DOI: 10.1186/1475-2875-11-64] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Accepted: 03/06/2012] [Indexed: 12/02/2022] Open
Abstract
WHO estimates that 80% of mortality due to malaria occurs among infants and young children. Though it has long been established that malaria disproportionately affects children under age five, our understanding of the underlying biological mechanisms for this distribution remains incomplete. Many studies use age as an indicator of exposure, but age may affect malaria burden independently of previous exposure. Not only does the severity of malaria infection change with age, but the clinical manifestation of disease does as well: younger children are more likely to suffer severe anaemia, while older children are more likely to develop cerebral malaria. Intensity of transmission and acquired immunity are important determinants of this age variation, but age differences remain consistent over varying transmission levels. Thus, age differences in clinical presentation may involve inherent age-related factors as well as still-undiscovered facets of acquired immunity, perhaps including the rates at which relevant aspects of immunity are acquired. The concept of "allometry" - the relative growth of a part in relation to that of an entire organism or to a standard - has not previously been applied in the context of malaria infection. However, because malaria affects a number of organs and cells, including the liver, red blood cells, white blood cells, and spleen, which may intrinsically develop at rates partly independent of each other and of a child's overall size, developmental allometry may influence the course and consequences of malaria infection. Here, scattered items of evidence have been collected from a variety of disciplines, aiming to suggest possible research paths for investigating exposure-independent age differences affecting clinical outcomes of malaria infection.
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Affiliation(s)
- Erica M W Billig
- Fogarty International Center, National Institutes of Health, Building 16, Bethesda, MD 20892, USA.
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Vieira-de-Abreu A, Campbell RA, Weyrich AS, Zimmerman GA. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 2011; 34:5-30. [PMID: 21818701 DOI: 10.1007/s00281-011-0286-4] [Citation(s) in RCA: 217] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Accepted: 07/20/2011] [Indexed: 12/28/2022]
Abstract
Platelets are chief effector cells in hemostasis. In addition, however, their specializations include activities and intercellular interactions that make them key effectors in inflammation and in the continuum of innate and adaptive immunity. This review focuses on the immune features of human platelets and platelets from experimental animals and on interactions between inflammatory, immune, and hemostatic activities of these anucleate but complex and versatile cells. The experimental findings and evidence for physiologic immune functions include previously unrecognized biologic characteristics of platelets and are paralleled by new evidence for unique roles of platelets in inflammatory, immune, and thrombotic diseases.
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Affiliation(s)
- Adriana Vieira-de-Abreu
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
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