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Binabaji S, Rahimi M, Rajabi H, Keshavarz M, Rahimi R, Ahmadi A, Gahreman D. Effects of physical training on coagulation parameters, interleukin-6, and angiotensin-converting enzyme-2 in COVID-19 survivors. Sci Rep 2024; 14:18968. [PMID: 39152162 PMCID: PMC11329640 DOI: 10.1038/s41598-024-67522-8] [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: 04/30/2024] [Accepted: 07/11/2024] [Indexed: 08/19/2024] Open
Abstract
COVID-19 is a highly contagious virus that uses Angiotensin-converting enzyme 2 (ACE2) as a receptor to enter human cells. The virus leads to an increase in inflammatory cytokines (i.e. IL-6) and an impaired coagulation system, which can cause serious complications during and after the disease. Physical exercise has been shown to improve COVID-19 complications through various mechanisms, such as modulation of the immune and coagulation systems. Therefore, this study investigated the effects of 8 weeks of training on inflammatory, coagulation, and physical factors in patients with COVID-19 during the recovery phase. Twenty-seven male and female volunteers (age 20-45 years) who recently recovered from COVID-19 were assigned to the control (n = 13) or the training group (n = 14). Blood samples, aerobic capacity and muscle endurance were collected 24 h before the start of the interventions and 24 h after the final training session in week 4 and 48 h after the final training session in week 8. IL-6, ACE2, fibrinogen, and D-dimer were measured using ELISA. The training group showed a significant increase in muscle endurance (p = 0.004) and aerobic capacity (p = 0.009) compared to the control group. Serum levels of IL-6 and fibrinogen decreased in the training group but this decrease was not statistically significant (p > 0.05). Despite a slight increase in the quality of life and sleep in the training group, no statistically significant difference was observed between the training and the control group. It appears that physical training has beneficial effects on the coagulation system, inflammatory factors, and sleep quality and can facilitate the recovery of COVID-19 patients.
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Affiliation(s)
- Soheila Binabaji
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Rahimi
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Hamid Rajabi
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran.
| | - Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Rahimeh Rahimi
- Department of Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Azam Ahmadi
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Daniel Gahreman
- Department of Sport, Exercise, Recreation, and Kinesiology, East Tennessee State University, Johnson City, TN, USA
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Pokhylko V, Cherniavska Y, Fishchuk L, Rossokha Z, Popova O, Vershyhora V, Ievseienkova O, Soloviova H, Zhuk L, Gorovenko N. Association of the C3953T (rs1143634) variant of the interleukin 1 beta gene with the features of a complicated course of COVID-19-associated pneumonia. Mol Biol Rep 2024; 51:630. [PMID: 38720147 DOI: 10.1007/s11033-024-09569-4] [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: 02/07/2024] [Accepted: 04/19/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND The pro-inflammatory cytokine IL-1 plays an important role in severe COVID-19. A change in IL-1 production may be associated with a mutation in the IL1Β gene. Our study analyzed the impact of the IL1Β gene variants (rs1143634) on disease progression in patients with severe COVID-19 pneumonia, taking into account treatment strategies. METHODS AND RESULTS The study enrolled 117 patients with severe COVID-19 pneumonia. The IL1Β gene variants were identified using the polymerase chain reaction-restriction fragment length polymorphism method. In the group of patients, the following genotype frequencies were found based on the investigated rs1143634 variant of the IL1Β gene: CC-65.8%, CT-28.2%, and TT-6.0%. Our results showed that the group of patients with the T allele of the IL1Β gene had higher leukocyte counts (p = 0.040) and more pronounced lymphopenia (p = 0.007). It was determined that patients carrying the T allele stayed on ventilators significantly longer (p = 0.049) and required longer treatment with corticosteroids (p = 0.045). CONCLUSION Identifying variants of the IL1Β gene can be used as a predictive tool for assessing the severity of COVID-19 pneumonia and tailoring personalized treatment strategies. Further research with a larger patient cohort is required to validate these findings.
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Affiliation(s)
| | | | - Liliia Fishchuk
- Department of Genetic Diagnostics, Institute of Genetic and Regenerative Medicine, SI "M.D. Strazhesko National Scientific Center of the NAMS of Ukraine", Kyiv, Ukraine.
| | - Zoia Rossokha
- SI "Reference-Center for Molecular Diagnostics of the Ministry of Public Health of Ukraine", Kyiv, Ukraine
| | - Olena Popova
- SI "Reference-Center for Molecular Diagnostics of the Ministry of Public Health of Ukraine", Kyiv, Ukraine
| | - Viktoriia Vershyhora
- SI "Reference-Center for Molecular Diagnostics of the Ministry of Public Health of Ukraine", Kyiv, Ukraine
| | - Olena Ievseienkova
- Department of Genetic Diagnostics, Institute of Genetic and Regenerative Medicine, SI "M.D. Strazhesko National Scientific Center of the NAMS of Ukraine", Kyiv, Ukraine
| | | | | | - Nataliia Gorovenko
- Department of Genetic Diagnostics, Institute of Genetic and Regenerative Medicine, SI "M.D. Strazhesko National Scientific Center of the NAMS of Ukraine", Kyiv, Ukraine
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Das T, Luo S, Tang H, Fang J, Mao Y, Yen HH, Dash S, Shajahan A, Pepi L, Huang S, Jones VS, Xie S, Huang GF, Lu J, Anderson B, Zhang B, Azadi P, Huang RP. N-glycosylation of the SARS-CoV-2 spike protein at Asn331 and Asn343 is involved in spike-ACE2 binding, virus entry, and regulation of IL-6. Microbiol Immunol 2024; 68:165-178. [PMID: 38444370 PMCID: PMC11273356 DOI: 10.1111/1348-0421.13121] [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: 07/31/2023] [Revised: 12/06/2023] [Accepted: 02/12/2024] [Indexed: 03/07/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global public health crisis. The causative agent, the SARS-CoV-2 virus, enters host cells via molecular interactions between the viral spike protein and the host cell ACE2 surface protein. The SARS-CoV-2 spike protein is extensively decorated with up to 66 N-linked glycans. Glycosylation of viral proteins is known to function in immune evasion strategies but may also function in the molecular events of viral entry into host cells. Here, we show that N-glycosylation at Asn331 and Asn343 of SARS-CoV-2 spike protein is required for it to bind to ACE2 and for the entry of pseudovirus harboring the SARS-CoV-2 spike protein into cells. Interestingly, high-content glycan binding screening data have shown that N-glycosylation of Asn331 and Asn343 of the RBD is important for binding to the specific glycan molecule G4GN (Galβ-1,4 GlcNAc), which is critical for spike-RBD-ACE2 binding. Furthermore, IL-6 was identified through antibody array analysis of conditioned media of the corresponding pseudovirus assay. Mutation of N-glycosylation of Asn331 and Asn343 sites of the spike receptor-binding domain (RBD) significantly reduced the transcriptional upregulation of pro-inflammatory signaling molecule IL-6. In addition, IL-6 levels correlated with spike protein levels in COVID-19 patients' serum. These findings establish the importance of RBD glycosylation in SARS-CoV-2 pathogenesis, which can be exploited for the development of novel therapeutics for COVID-19.
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Affiliation(s)
- Tuhin Das
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Shuhong Luo
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
- RayBiotech Guangzhou Co. Ltd. Guangzhou, No. 79 Ruihe Road, Huangpu District, Guangzhou, China
| | - Hao Tang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
- RayBiotech Guangzhou Co. Ltd. Guangzhou, No. 79 Ruihe Road, Huangpu District, Guangzhou, China
| | - Jianmin Fang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
- RayBiotech Guangzhou Co. Ltd. Guangzhou, No. 79 Ruihe Road, Huangpu District, Guangzhou, China
| | - Yinging Mao
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Haw-Han Yen
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Sabyasachi Dash
- Weill Cornell Medicine, Department of Pathology, Center for Vascular Biology, New York. NY. 10065. USA
| | - Asif Shajahan
- Vaccine Research Center, National Institutes of Health, Gaithersburg, MD, 20788, USA
| | - Lauren Pepi
- Vaccine Research Center, National Institutes of Health, Gaithersburg, MD, 20788, USA
| | - Steven Huang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Valerie S. Jones
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Shehuo Xie
- RayBiotech Guangzhou Co. Ltd. Guangzhou, No. 79 Ruihe Road, Huangpu District, Guangzhou, China
| | - Gordon F. Huang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Jinqiao Lu
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Blake Anderson
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Benyue Zhang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Parastoo Azadi
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
| | - Ruo-Pan Huang
- RayBiotech Life Inc., 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
- RayBiotech Guangzhou Co. Ltd. Guangzhou, No. 79 Ruihe Road, Huangpu District, Guangzhou, China
- South China Biochip Research Center, Guangzhou, China 510630
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Medical University, China 510095
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Oatis D, Herman H, Balta C, Ciceu A, Simon-Repolski E, Mihu AG, Lepre CC, Russo M, Trotta MC, Gravina AG, D’Amico M, Hermenean A. Dynamic shifts in lung cytokine patterns in post-COVID-19 interstitial lung disease patients: a pilot study. Ther Adv Chronic Dis 2024; 15:20406223241236257. [PMID: 38560720 PMCID: PMC10981850 DOI: 10.1177/20406223241236257] [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: 08/19/2023] [Accepted: 02/14/2024] [Indexed: 04/04/2024] Open
Abstract
INTRODUCTION The pathogenesis of post-COVID interstitial lung disease, marked by lung tissue scarring and functional decline, remains largely unknown. OBJECTIVES We aimed to elucidate the temporal cytokine/chemokine changes in bronchoalveolar lavage (BAL) from patients with post-COVID interstitial lung disease to uncover potential immune drivers of pulmonary complications. DESIGN We evaluated 16 females diagnosed with post-COVID interstitial lung disease, originating from moderate to severe cases during the second epidemic wave in the Autumn of 2020, treated at the Pneumology Department of the Arad County Clinical Hospital, Romania. Their inflammatory response over time was compared to a control group. METHODS A total of 48 BAL samples were collected over three intervals (1, 3, and 6 months) and underwent cytology, gene, and protein expression analyses for pro/anti-inflammatory lung cytokines and chemokines using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS One month after infection, there were significant increases in the levels of IL-6 and IL-8. These levels decreased gradually over the course of 6 months but were still higher than those seen in control. Interferon-gamma and tumor necrosis factor alpha exhibited similar patterns. Persistent elevations were found in IL-10, IL-13, and pro-fibrotic M2 macrophages' chemokines (CCL13 and CCL18) for 6 months. Furthermore, pronounced neutrophilia was observed at 1 month post-COVID, highlighting persistent inflammation and lung damage. Neutrophil efferocytosis, aiding inflammation resolution and tissue repair, was evident at the 1-month time interval. A notable time-dependent reduction in CD28 was also noticed. CONCLUSION Our research provides insight into the immunological processes that may lead to the fibrotic changes noted in the lungs following COVID-19.
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Affiliation(s)
- Daniela Oatis
- Department of Infectious Disease, Faculty of Medicine, “Vasile Goldis” Western University of Arad, Arad, Romania
- Multidisciplinary Doctoral School, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Hildegard Herman
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Cornel Balta
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Alina Ciceu
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Erika Simon-Repolski
- Department of Pneumology, Faculty of Medicine, “Vasile Goldis” Western University of Arad, Arad, Romania
- Department of Pneumology, Arad Clinical Emergency Hospital, Arad, Romania
| | - Alin Gabriel Mihu
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Caterina Claudia Lepre
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marina Russo
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine and Complex Operative Unit of Hepatogastroenterology and Digestive Endoscopy, University Hospital, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Michele D’Amico
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Anca Hermenean
- Department of Histology, Faculty of Medicine, “Vasile Goldis” Western University of Arad, 94-96 Revolutiei Av., Arad 310025, Romania
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Shyamsundar S, Pierson SK, Connolly CM, Teles M, Segev DL, Werbel WA, van Rhee F, Casper C, Brandstadter JD, Noy A, Fajgenbaum DC. Castleman disease patients report mild COVID-19 symptoms and mount a humoral response to SARS-CoV-2 vaccination. BLOOD NEOPLASIA 2024; 1:100002. [PMID: 39044861 PMCID: PMC11265787 DOI: 10.1016/j.bneo.2024.100002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
The coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the pro-inflammatory cytokine, interleukin 6 (IL6). As Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL6 inhibition, we sought to evaluate outcomes following COVID-19 and SARS-CoV-2 vaccination in CD patients. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 CD patients enrolled in ACCELERATE, a natural history registry of CD patients. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose one (62/112, 55%) were comparable to the general U.S. population. While there were two cases of CD flares occurring shortly after SARS-CoV-2 infection (N=1) and vaccination (N=1), over 100 patients in this study that were infected and/or vaccinated did not experience CD flares. The median anti-spike titer six months after the second dose among CD patients was comparable to individuals with other immune-related diseases and healthy populations. Data from this small cohort suggest that, despite being on immunosuppressive therapies, CD patients do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered on clinicaltrials.gov (#NCT02817997).
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Affiliation(s)
- Saishravan Shyamsundar
- Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sheila K. Pierson
- Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Caoilfhionn M. Connolly
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA
| | - Mayan Teles
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA
| | - Dorry L. Segev
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, 10016, USA
| | - William A. Werbel
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA
| | - Frits van Rhee
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Corey Casper
- Access to Advanced Health Institute, Seattle, WA, 98102, USA
- Department of Global Health, University of Washington, Seattle, WA, 98105, USA
- Department of Medicine, University of Washington, Seattle, WA, 98195, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Joshua D. Brandstadter
- Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ariela Noy
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Weill Cornell Medical College, New York, NY, 10065, USA
| | - David C. Fajgenbaum
- Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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Khanaliha K, Sadri Nahand J, Khatami A, Mirzaei H, Chavoshpour S, Taghizadieh M, Karimzadeh M, Donyavi T, Bokharaei‐Salim F. Analyzing the expression pattern of the noncoding RNAs (HOTAIR, PVT-1, XIST, H19, and miRNA-34a) in PBMC samples of patients with COVID-19, according to the disease severity in Iran during 2022-2023: A cross-sectional study. Health Sci Rep 2024; 7:e1861. [PMID: 38332929 PMCID: PMC10850438 DOI: 10.1002/hsr2.1861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/10/2024] Open
Abstract
Background and aims MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are well-known types of noncoding RNAs (ncRNAs), which have been known as the key regulators of gene expression. They can play critical roles in viral infection by regulating the host immune response and interacting with genes in the viral genome. In this regard, ncRNAs can be employed as biomarkers for viral diseases. The current study aimed to evaluate peripheral blood mononuclear cell (PBMC) ncRNAs (lncRNAs-homeobox C antisense intergenic RNA [HOTAIR], -H19, X-inactive-specific transcript [XIST], plasmacytoma variant translocation 1 [PVT-1], and miR-34a) as diagnostic biomarkers to differentiate severe COVID-19 cases from mild ones. Methods Candidate ncRNAs were selected according to previous studies and assessed by real-time polymerase chain reaction in the PBMC samples of patients with severe coronavirus disease 2019 (COVID-19) (n = 40), healthy subjects (n = 40), and mild COVID-19 cases (n = 40). Furthermore, the diagnostic value of the selected ncRNAs was assessed by analyzing the receiver-operating characteristic (ROC). Results The results demonstrated that the expression pattern of the selected ncRNAs was significantly different between the studied groups. The levels of HOTAIR, XIST, and miR-34a were remarkably overexpressed in the severe COVID-19 group in comparison with the mild COVID-19 group, and in return, the PVT-1 levels were lower than in the mild COVID-19 group. Interestingly, the XIST expression level in men with severe COVID-19 was higher compared to women with mild COVID-19. ROC results suggested that HOTAIR and PVT-1 could serve as useful biomarkers for screening mild COVID-19 from severe COVID-19. Conclusions Overall, different expression patterns of the selected ncRNAs and ROC curve results revealed that these factors can contribute to COVID-19 pathogenicity and can be considered diagnostic markers of COVID-19 severe outcomes.
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Affiliation(s)
- Khadijeh Khanaliha
- Research Center of Pediatric Infectious Diseases, Institute of Immunology and Infectious DiseasesIran University of Medical SciencesTehranIran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | - AliReza Khatami
- Department of VirologyIran University of Medical SciencesTehranIran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic DiseasesKashan University of Medical SciencesKashanIran
| | - Sara Chavoshpour
- Department of VirologyTehran University of Medical SciencesTehranIran
| | - Mohammad Taghizadieh
- Department of Pathology, Faculty of MedicineTabriz University of Medical SciencesTabrizIran
| | - Mohammad Karimzadeh
- Core Research Facilities (CRF)Isfahan University of Medical ScienceIsfahanIran
| | - Tahereh Donyavi
- Department of Medical Biotechnology, Faculty of Allied MedicineIran University of Medical SciencesTehranIran
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Elnosary ME, Shreadah MA, Ashour ML, Nabil-Adam A. Predictions based on inflammatory cytokine profiling of Egyptian COVID-19 with 2 potential therapeutic effects of certain marine-derived compounds. Int Immunopharmacol 2024; 126:111072. [PMID: 38006751 DOI: 10.1016/j.intimp.2023.111072] [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: 11/12/2022] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 11/27/2023]
Abstract
BACKGROUNDS A worldwide coronavirus pandemic has affected many healthcare systems in 2019 (COVID-19). Following viral activation, cytokines and chemokines are released, causing inflammation and tissue death, particularly in the lungs, resulting in severe COVID-19 symptoms such as pneumonia and ARDS. COVID-19 induces the release of several chemokines and cytokines in different organs, such as the cardiovascular system and lungs. RESEARCH IDEA COVID-19 and its more severe effects, such as an elevated risk of death, are more common in patients with metabolic syndrome and the elderly. Cytokine storm and COVID-19 severity may be mitigated by immunomodulation targeting NF-κB activation in conjunction with TNF- α -inhibition. In severe cases of COVID-19, inhibiting the NF-κB/TNF- α, the pathway may be employed as a therapeutic option. MATERIAL AND METHODS The study will elaborate on the Egyptian pattern for COVID-19 patients in the first part of our study. An Egyptian patient with COVID-19 inflammatory profiling will be discussed in the second part of this article using approved marine drugs selected to inhabit the significant inflammatory signals. A biomarker profiling study is currently being performed on Egyptian patients with SARS-COV-2. According to the severity of the infection, participants were divided into four groups. The First Group was non-infected with SARS-CoV-2 (Control, n = 16), the Second Group was non-intensive care patients (non-ICU, n = 16), the Third Group was intensive care patients (ICU, n = 16), and the Fourth Group was ICU with endotracheal intubation (ICU + EI, n = 16). To investigate COVID-19 inflammatory biomarkers for Egyptian patients, several inflammatory, oxidative, antioxidant, and anti-inflammatory biomarkers were measured. The following are examples of blood tests: CRP, Ferritin, D-dimer, TNF-α, IL-8, IL-6., IL-Ib, CD8, NF-κB, MDA, and total antioxidants. RESULTS AND DISCUSSION The results of the current study revealed many logical findings, such as the elevation of CRP, Ferritin, D-dimer, TNF- α, CD8, IL-6, IL-, NF-κB, and MDA. Where a significant increase showed in ICU group results (23.05 ± 0.30, 2.35 ± 0.86, 433.4 ± 159.3, 26.67 ± 3.51, 7.52 ± 1.48, 7.49 ± 1.04, 5.76 ± 1.31, 7.41 ± 0.73) respectively, and also ICU group results (54.75 ± 3.44, 0.65 ± 0.13, 460.2 ± 121.42, 27.43 ± 2.52, 8.63 ± 2.68, 10.65 ± 2.75, 5.93 ± 1.4, 10.64 ± 0.86) respectively, as well as ICU + EI group results (117.63 ± 11.89, 1.22 ± 0.65, 918.8 ± 159.27, 26.68 ± 2.00, 6.68 ± 1.08, 11.68 ± 6.16, 6.23 ± 0.07, 22.41 ± 1.39),respectively.The elevation in laboratory biomarkers of cytokines storm in three infected groups with remarkable increases in the ICU + EI group was due to the elevation of oxidative stress and inflammatory storm molecules, which lead to highly inflammatory responses, specifically in severe patients of COVID-19. Another approach to be used in the current study is investigating new computational drug compounds for SARS-COV-2 protective agents from the marine environment. The results revealed that (Imatinib and Indinavir) had the highest affinity toward Inflammatory molecules and COVID-19 proteins (PDB ID: -7CZ4 and 7KJR), which may be used in the future as possible COVID-19 drug candidates. CONCLUSION The investigated inflammatory biomarkers in Egyptian COVID-19 patients showed a strong correlation between IL6, TNF-α, NF-κB, CRB, DHL, and ferritin as COVID-19 biomarkers and determined the severity of the infection. Also, the oxidative /antioxidant showed good biomarkers for infection recovery and progression of the patients.
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Affiliation(s)
- Mohamed E Elnosary
- Al-Azhar University, Faculty of Science, Botany and Microbiology Department, 11884 Nasr City, Cairo, Egypt.
| | - Mohamed Attia Shreadah
- Marine Biotechnology and Natural Products Laboratory, National Institute of Oceanography & Fisheries, Egypt
| | - Mohamed L Ashour
- Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Abbasia, Cairo 11566, Egypt; Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia.
| | - Asmaa Nabil-Adam
- Marine Biotechnology and Natural Products Laboratory, National Institute of Oceanography & Fisheries, Egypt.
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Wolszczak-Biedrzycka B, Dorf J, Wojewódzka-Żelezniakowicz M, Żendzian-Piotrowska M, Dymicka-Piekarska V, Matowicka-Karna J, Maciejczyk M. Changes in chemokine and growth factor levels may be useful biomarkers for monitoring disease severity in COVID-19 patients; a pilot study. Front Immunol 2024; 14:1320362. [PMID: 38239363 PMCID: PMC10794366 DOI: 10.3389/fimmu.2023.1320362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/11/2023] [Indexed: 01/22/2024] Open
Abstract
Aim The aim of the present study was to assess differences in the serum levels of chemokines and growth factors (GFs) between COVID-19 patients and healthy controls. The diagnostic utility of the analyzed proteins for monitoring the severity of the SARS-CoV- 2 infection based on the patients' MEWS scores was also assessed. Materials and methods The serum levels of chemokines and growth factors were analyzed in hospitalized COVID-19 patients (50 women, 50 men) with the use of the Bio-Plex Pro™ Human Cytokine Screening Panel (Biorad) and the Bio-Plex Multiplex system. Results The study demonstrated that serum levels of MIP-1α, RANTES, Eotaxin, CTACK, GRO-α, IP-10, MIG, basic-FGF, HGF, SCGF-β, G-CSF, M-CSF, SCF, MIF, LIF, and TRAIL were significant higher in COVID-19 patients than in the control group. The concentrations of CTACK, GRO-α, IP-10, MIG, basic-FGF, HGF, PDGF- BB, GM-CSF, SCF, LIF, and TRAIL were higher in asymptomatic/mildly symptomatic COVID-19 patients (stage 1) and COVID-19 patients with pneumonia without respiratory failure (stage 2). The receiver operating characteristic (ROC) analysis revealed that IP-10, MIF, MIG, and basic-FGF differentiated patients with COVID-19 from healthy controls with the highest sensitivity and specificity, whereas GM-CSF, basic-FGF, and MIG differentiated asymptomatic/mildly symptomatic COVID-19 patients (stage 1) from COVID-19 patients with pneumonia without respiratory failure (stage 2) with the highest sensitivity and specificity. Conclusions MIG, basic-FGF, and GM-CSF can be useful biomarkers for monitoring disease severity in patients with COVID-19.
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Affiliation(s)
- Blanka Wolszczak-Biedrzycka
- Department of Psychology and Sociology of Health and Public Health, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Justyna Dorf
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | | | | | | | - Joanna Matowicka-Karna
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland
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9
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Aiges M, Ramana KV. Significance of Vitamin Supplementation in Reducing the Severity of COVID-19. Mini Rev Med Chem 2024; 24:254-264. [PMID: 36967461 DOI: 10.2174/1389557523666230324081713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/24/2022] [Accepted: 01/11/2023] [Indexed: 03/29/2023]
Abstract
Coronavirus disease-19 (COVID-19), a serious pandemic due to the SARS-CoV-2 virus infection, caused significant lockdowns, healthcare shortages, and deaths worldwide. The infection leads to an uncontrolled systemic inflammatory response causing severe respiratory distress and multiple-organ failure. Quick development of several vaccines efficiently controlled the spread of COVID-19. However, the rise of various new subvariants of COVID-19 demonstrated some concerns over the efficacy of existing vaccines. Currently, better vaccines to control these variants are still under development as several new subvariants of COVID-19, such as omicron BA-4, BA-5, and BF-7 are still impacting the world. Few antiviral treatments have been shown to control COVID-19 symptoms. Further, control of COVID-19 symptoms has been explored with many natural and synthetic adjuvant compounds in hopes of treating the deadly and contagious disease. Vitamins have been shown to modulate the immune system, function as antioxidants, and reduce the inflammatory response. Recent studies have investigated the potential role of vitamins, specifically vitamins A, B, C, D, and E, in reducing the immune and inflammatory responses and severity of the complication. In this brief article, we discussed our current understanding of the role of vitamins in controlling COVID-19 symptoms and their potential use as adjuvant therapy.
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Affiliation(s)
- Myia Aiges
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT-84606, USA
| | - Kota V Ramana
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT-84606, USA
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10
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Makled AF, Ali SAM, Eldahdouh SS, Sleem AS, Eldahshan MM, Elsaadawy Y, Salman SS, Mohammed Elbrolosy A. Angiotensin-Converting Enzyme-2 ( ACE-2) with Interferon-Induced Transmembrane Protein-3 ( IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population. Int J Microbiol 2023; 2023:6384208. [PMID: 38155729 PMCID: PMC10754637 DOI: 10.1155/2023/6384208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/21/2023] [Accepted: 12/08/2023] [Indexed: 12/30/2023] Open
Abstract
Introduction The host genetic background is a crucial factor that underlies the interindividual variability of COVID-19 fatality and outcomes. Angiotensin-converting enzyme-2 (ACE-2) and interferon-induced transmembrane protein-3 (IFITM-3) have a key role in viral cell entrance and priming. The evoked immune response will also provide a predictive prognosis for COVID-19 infection. This study aimed to explore the association between ACE-2 and IFITM-3 genotypes and their corresponding allele frequencies with disease severity indices in the Egyptian COVID-19 population. The serum level of interleukin-6, as a biomarker of hyperinflammatory response, and cytokine storm, was correlated with disease progression, single nucleotide polymorphisms (SNPs) of the selected receptors, and treatment response. Methodology. We enrolled 900 COVID-19-confirmed cases and 100 healthy controls. Genomic DNA was extracted from 200 subjects (160 patients selected based on clinical and laboratory data and 40 healthy controls). The ACE-2 rs2285666 and IFITM-3 rs12252 SNPs were genotyped using the TaqMan probe allelic discrimination assay, and the serum IL-6 level was determined by ELISA. Logistic regression analysis was applied to analyze the association between ACE-2 and IFITM-3 genetic variants, IL-6 profile, and COVID-19 severity. Results The identified genotypes and their alleles were significantly correlated with COVID-19 clinical deterioration as follows: ACE2 rs2285666 CT + TT, odds ratio (95% confidence interval): 12.136 (2.784-52.896) and IFITM-3 rs12252 AG + GG: 17.276 (3.673-81.249), both p < 0.001. Compared to the controls, the heterozygous and mutant genotypes for both SNPs were considerable risk factors for increased susceptibility to COVID-19. IL-6 levels were significantly correlated with disease progression (p < 0.001). Conclusion ACE-2 and IFITM-3 genetic variants are potential predictors of COVID-19 severity, critical outcomes, and post-COVID-19 complications. Together, these SNPs and serum IL-6 levels explain a large proportion of the variability in the severity of COVID-19 infection and its consequences among Egyptian subjects.
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Affiliation(s)
- Amal F. Makled
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - Sahar A. M. Ali
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - S. S. Eldahdouh
- Department of Chest Diseases and Tuberculosis, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - Asmaa S. Sleem
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - Maha M. Eldahshan
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - Yara Elsaadawy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Samar S. Salman
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
| | - Asmaa Mohammed Elbrolosy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin al Kom, Egypt
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11
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Wolszczak-Biedrzycka B, Dorf J, Wojewódzka-Żelezniakowicz M, Żendzian-Piotrowska M, Dymicka-Piekarska VJ, Matowicka-Karna J, Maciejczyk M. Unveiling COVID-19 Secrets: Harnessing Cytokines as Powerful Biomarkers for Diagnosis and Predicting Severity. J Inflamm Res 2023; 16:6055-6070. [PMID: 38107380 PMCID: PMC10723593 DOI: 10.2147/jir.s439217] [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: 10/08/2023] [Accepted: 11/21/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction In coronavirus disease (COVID-19), inflammation takes center stage, with a cascade of cytokines released, contributing to both inflammation and lung damage. The objective of this study is to identify biomarkers for diagnosing and predicting the severity of COVID-19. Materials and Methods Cytokine levels were determined in the serum from venous blood samples collected from 100 patients with COVID-19 and 50 healthy controls. COVID-19 patients classified based on the Modified Early Warning (MEWS) score. Cytokine concentrations were determined with a multiplex ELISA kit (Bio-Plex Pro™ Human Cytokine Screening Panel). Results The concentrations of all analyzed cytokines were elevated in the serum of COVID-19 patients relative to the control group, but no significant differences were observed in interleukin-9 (IL-9) and IL-12 p70 levels. In addition, the concentrations of IL-1α, IL-1β, IL-1ra, IL-2Rα, IL-6, IL-12 p40, IL-18, and tumor necrosis factor alpha (TNFα) were significantly higher in symptomatic patients with accompanying pneumonia without respiratory failure (stage 2) than in asymptomatic/mildly symptomatic patients (stage 1). Conclusion The study revealed that IL-1ra, IL-2Rα, IL-6, IL-8, IL-12 p40, IL-16, and IL-18 levels serve as potential diagnostic biomarkers in COVID-19 patients. Furthermore, elevated IL-1α levels proved to be valuable in assessing the severity of COVID-19.
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Affiliation(s)
- Blanka Wolszczak-Biedrzycka
- Department of Psychology and Sociology of Health and Public Health, University of Warmia and Mazury in Olsztyn, Olsztyn, 10-900, Poland
| | - Justyna Dorf
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, 15-089, Poland
| | | | | | | | - Joanna Matowicka-Karna
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, 15-089, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, 15-089, Poland
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12
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Pencheva M, Bozhkova M, Kalchev Y, Petrov S, Baldzhieva A, Kalfova T, Dichev V, Keskinova D, Genova S, Atanasova M, Murdzheva M. The Serum ACE2, CTSL, AngII, and TNFα Levels after COVID-19 and mRNA Vaccines: The Molecular Basis. Biomedicines 2023; 11:3160. [PMID: 38137381 PMCID: PMC10741205 DOI: 10.3390/biomedicines11123160] [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: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND The SARS-CoV-2 virus as well as the COVID-19 mRNA vaccines cause an increased production of proinflammatory cytokines. AIM We investigated the relationship between ACE2, CTSL, AngII, TNFα and the serum levels of IL-6, IL-10, IL-33, IL-28A, CD40L, total IgM, IgG, IgA and absolute count of T- and B-lymphocytes in COVID-19 patients, vaccinees and healthy individuals. METHODS We measured the serum levels ACE2, AngII, CTSL, TNFα and humoral biomarkers (CD40L, IL-28A, IL-10, IL-33) by the ELISA method. Immunophenotyping of lymphocyte subpopulations was performed by flow cytometry. Total serum immunoglobulins were analyzed by the turbidimetry method. RESULTS The results established an increase in the total serum levels for ACE2, CTSL, AngII and TNFα by severely ill patients and vaccinated persons. The correlation analysis described a positive relationship between ACE2 and proinflammatory cytokines IL-33 (r = 0.539) and CD40L (r = 0.520), a positive relationship between AngII and CD40L (r = 0.504), as well as between AngII and IL-33 (r = 0.416), and a positive relationship between CTSL, total IgA (r = 0.437) and IL-28A (r = 0.592). Correlation analysis confirmed only two of the positive relationships between TNFα and IL-28A (r = 0.491) and CD40L (r = 0.458). CONCLUSIONS In summary, the findings presented in this study unveil a complex web of interactions within the immune system in response to SARS-CoV-2 infection and vaccination.
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Affiliation(s)
- Mina Pencheva
- Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Martina Bozhkova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Yordan Kalchev
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Steliyan Petrov
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Alexandra Baldzhieva
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Teodora Kalfova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Valentin Dichev
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Donka Keskinova
- Department of Applied and Institutional Sociology, Faculty of Philosophy and History, University of Plovdiv “Paisii Hilendarski”, 4000 Plovdiv, Bulgaria;
| | - Silvia Genova
- Department of General and Clinical Pathology, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Mariya Atanasova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Laboratory of Virology, UMBAL “St. George” EAD, 4002 Plovdiv, Bulgaria
| | - Mariana Murdzheva
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
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Hafizi M, Kalanaky S, Fakharzadeh S, Karimi P, Fakharian A, Lookzadeh S, Mortaz E, Mirenayat MS, Heshmatnia J, Karam MB, Zamani H, Nadji A, Toutkaboni MP, Oraee-Yazdani S, Akbari ME, Jamaati H, Nazaran MH. Beneficial effects of the combination of BCc1 and Hep-S nanochelating-based medicines on IL-6 in hospitalized moderate COVID-19 adult patients: a randomized, double-blind, placebo-controlled clinical trial. Trials 2023; 24:720. [PMID: 37951972 PMCID: PMC10638761 DOI: 10.1186/s13063-023-07624-2] [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: 11/08/2022] [Accepted: 09/05/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND In the severe forms of COVID-19 and many other infectious diseases, the patients develop a cytokine storm syndrome (CSS) where pro-inflammatory cytokines such as IL-6 and TNF-α play a key role in the development of this serious process. Selenium and iron are two important trace minerals, and their metabolism is tightly connected to immune system function. Numerous studies highlight the role of selenium and iron metabolism changes in the procedure of COVID-19 inflammation. The immunomodulator effect of nanomedicines that are synthesized based on nanochelating technology has been proved in previous studies. In the present study, the effects of the combination of BCc1(with iron-chelating property) and Hep-S (containing selenium) nanomedicines on mentioned cytokines levels in hospitalized moderate COVID-19 patients were evaluated. METHODS Laboratory-confirmed moderate COVID-19 patients were enrolled to participate in a randomized, double-blind, placebo-controlled study in two separate groups: combination of BCc1 and Hep-S (N = 62) (treatment) or placebo (N = 60) (placebo). The blood samples were taken before medications on day zero, at discharge, and 28 days after consumption to measure hematological and biochemical parameters and cytokine levels. The clinical symptoms of all the patients were recorded according to an assessment questionnaire before the start of the treatment and on days 3 and discharge day. RESULTS The results revealed that consumption of the nanomedicines led to a significant decrease in the mean level of IL-6 cytokine, and at the end of the study, there was a 77% downward trend in IL-6 in the nanomedicine group, while an 18% increase in the placebo group (p < 0.05). In addition, the patients in the nanomedicines group had lower TNF-α levels; accordingly, there was a 21% decrease in TNF-α level in the treatment group, while a 31% increase in this cytokine level in the placebo was observed (p > 0.05). On the other hand, in nanomedicines treated groups, clinical scores of coughing, fatigue, and need for oxygen therapy improved. CONCLUSIONS In conclusion, the combination of BCc1 and Hep-S inhibits IL-6 as a highly important and well-known cytokine in COVID-19 pathophysiology and presents a promising view for immunomodulation that can manage CSS. TRIAL REGISTRATION Iranian Registry of Clinical Trials RCT20170731035423N2 . Registered on June 12, 2020.
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Affiliation(s)
- Maryam Hafizi
- Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran
| | - Somayeh Kalanaky
- Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran
| | - Saideh Fakharzadeh
- Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran
| | - Pegah Karimi
- Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran
| | - Atefeh Fakharian
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Lookzadeh
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Esmaeil Mortaz
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Sadat Mirenayat
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jalal Heshmatnia
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Bakhshayesh Karam
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homa Zamani
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Nadji
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mihan Pourabdollah Toutkaboni
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Comprehensive Neurosurgical Center of Excellence, Shohada Tajrish, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hamidreza Jamaati
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Zarrabi M, Shahrbaf MA, Nouri M, Shekari F, Hosseini SE, Hashemian SMR, Aliannejad R, Jamaati H, Khavandgar N, Alemi H, Madani H, Nazari A, Amini A, Hassani SN, Abbasi F, Jarooghi N, Fallah N, Taghiyar L, Ganjibakhsh M, Hajizadeh-Saffar E, Vosough M, Baharvand H. Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial. Stem Cell Res Ther 2023; 14:169. [PMID: 37365605 PMCID: PMC10294333 DOI: 10.1186/s13287-023-03402-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 06/15/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND AND AIMS The main causes of death in patients with severe Coronavirus disease-2019 (COVID-19) are acute respiratory distress syndrome (ARDS) and multiorgan failure caused by a severe inflammatory cascade. Novel treatment strategies, such as stem-cell-based therapy and their derivatives can be used to relieve inflammation in these cases. In this study, we aimed to evaluate the safety and efficacy of therapy using mesenchymal stromal cells (MSCs) and their derived extracellular vesicles in COVID-19 patients. MATERIALS AND METHODS COVID-19 patients with ARDS were included in this study and allocated into two study and control groups using block randomization. While all patients received recommended treatment based on guidelines from the national advisory committee for COVID-19 pandemic, the two intervention groups received two consecutive injections of MSCs (100 × 106 cells) or one dose of MSCs (100 × 106 cells) followed by one dose of MSC-derived extracellular vesicles (EVs). Patients were assessed for safety and efficacy by evaluating clinical symptoms, laboratory parameters, and inflammatory markers at baseline and 48 h after the second intervention. RESULTS A total number of 43 patients (the MSC alone group = 11, MSC plus EV group = 8, and control group = 24) were included in the final analysis. Mortality was reported in three patients in the MSC alone group (RR: 0.49; 95% CI 0.14-1.11; P = 0.08); zero patient in the MSC plus EV group (RR: 0.08; 95% CI 0.005-1.26; P = 0.07) and eight patients in the control group. MSC infusion was associated with a decrease in inflammatory cytokines such as IL-6 (P = 0.015), TNF-α (P = 0.034), IFN-γ (P = 0.024), and CRP (P = 0.041). CONCLUSION MSCs and their extracellular vesicles can significantly reduce the serum levels of inflammatory markers in COVID-19 patients, with no serious adverse events. Trial registration IRCT, IRCT registration number: IRCT20200217046526N2. Registered 13th April 2020, http://www.irct.ir/trial/47073 .
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Affiliation(s)
- Morteza Zarrabi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Amin Shahrbaf
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masoumeh Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyedeh-Esmat Hosseini
- Nursing and Midwifery Care Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed-Mohammad Reza Hashemian
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Aliannejad
- Pulmonary Department, Thoracic Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naghmeh Khavandgar
- Pulmonary Department, Thoracic Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Alemi
- Pulmonary Department, Thoracic Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Madani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abdoreza Nazari
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azadeh Amini
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyedeh Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Abbasi
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Jarooghi
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nasrin Fallah
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Leila Taghiyar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Meysam Ganjibakhsh
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Ensiyeh Hajizadeh-Saffar
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Hossein Baharvand
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
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15
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Kane AS, Boribong BP, Loiselle M, Chitnis AP, Chavez H, Moldawer LL, Larson SD, Badaki-Makun O, Irimia D, Yonker LM. Monocyte anisocytosis corresponds with increasing severity of COVID-19 in children. Front Pediatr 2023; 11:1177048. [PMID: 37425266 PMCID: PMC10326545 DOI: 10.3389/fped.2023.1177048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Introduction Although SARS-CoV-2 infection can lead to severe COVID-19 in children, the role of biomarkers for assessing the risk of progression to severe disease is not well established in the pediatric population. Given the differences in monocyte signatures associated with worsening COVID-19 in adults, we aimed to determine whether monocyte anisocytosis early in the infectious course would correspond with increasing severity of COVID-19 in children. Methods We performed a multicenter retrospective study of 215 children with SARS-CoV-2 infection, Multisystem Inflammatory Syndrome in Children (MIS-C), convalescent COVID-19, and healthy age-matched controls to determine whether monocyte anisocytosis, quantified by monocyte distribution width (MDW) on complete blood count, was associated with increasing severity of COVID-19. We performed exploratory analyses to identify other hematologic parameters in the inflammatory signature of pediatric SARS-CoV-2 infection and determine the most effective combination of markers for assessing COVID-19 severity in children. Results Monocyte anisocytosis increases with COVID-19 severity and need for hospitalization. Although other inflammatory markers such as lymphocyte count, neutrophil/lymphocyte ratio, C-reactive protein, and cytokines correlate with disease severity, these parameters were not as sensitive as MDW for identifying severe disease in children. An MDW threshold of 23 offers a sensitive marker for severe pediatric COVID-19, with improved accuracy when assessed in combination with other hematologic parameters. Conclusion Monocyte anisocytosis corresponds with shifting hematologic profiles and inflammatory markers in children with COVID-19, and MDW serves as a clinically accessible biomarker for severe COVID-19 in children.
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Affiliation(s)
- Abigail S. Kane
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
| | - Brittany P. Boribong
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Maggie Loiselle
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
| | - Anagha P. Chitnis
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
| | - Hector Chavez
- Department of Pediatrics, Jackson Memorial Hospital, Miami, FL, United States
- Department of Pediatric Emergency Medicine, Holtz Children’s Hospital, Miami, FL, United States
| | - Lyle L. Moldawer
- Department of Surgery, University of Florida, Gainesville, FL, United States
| | - Shawn D. Larson
- Department of Surgery, University of Florida, Gainesville, FL, United States
| | - Oluwakemi Badaki-Makun
- Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Center for Data Science in Emergency Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Daniel Irimia
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA, United States
- Department of Surgery, Shriners Burn Hospital, Boston, MA, United States
| | - Lael M. Yonker
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
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16
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Hossain MA, Sohel M, Sultana T, Hasan MI, Khan MS, Kibria KMK, Mahmud SMH, Rahman MH. Study of kaempferol in the treatment of COVID-19 combined with Chikungunya co-infection by network pharmacology and molecular docking technology. INFORMATICS IN MEDICINE UNLOCKED 2023; 40:101289. [PMID: 37346467 PMCID: PMC10264333 DOI: 10.1016/j.imu.2023.101289] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Chikungunya (CHIK) patients may be vulnerable to coronavirus disease (COVID-19). However, presently there are no anti-COVID-19/CHIK therapeutic alternatives available. The purpose of this research was to determine the pharmacological mechanism through which kaempferol functions in the treatment of COVID-19-associated CHIK co-infection. We have used a series of network pharmacology and computational analysis-based techniques to decipher and define the binding capacity, biological functions, pharmacological targets, and treatment processes in COVID-19-mediated CHIK co-infection. We identified key therapeutic targets for COVID-19/CHIK, including TP53, MAPK1, MAPK3, MAPK8, TNF, IL6 and NFKB1. Gene ontology, molecular and upstream pathway analysis of kaempferol against COVID-19 and CHIK showed that DEGs were confined mainly to the cytokine-mediated signalling pathway, MAP kinase activity, negative regulation of the apoptotic process, lipid and atherosclerosis, TNF signalling pathway, hepatitis B, toll-like receptor signaling, IL-17 and IL-18 signaling pathways. The study of the gene regulatory network revealed several significant TFs including KLF16, GATA2, YY1 and FOXC1 and miRNAs such as let-7b-5p, mir-16-5p, mir-34a-5p, and mir-155-5p that target differential-expressed genes (DEG). According to the molecular coupling results, kaempferol exhibited a high affinity for 5 receptor proteins (TP53, MAPK1, MAPK3, MAPK8, and TNF) compared to control inhibitors. In combination, our results identified significant targets and pharmacological mechanisms of kaempferol in the treatment of COVID-19/CHIK and recommended that core targets be used as potential biomarkers against COVID-19/CHIK viruses. Before conducting clinical studies for the intervention of COVID-19 and CHIK, kaempferol might be evaluated in wet lab tests at the molecular level.
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Affiliation(s)
- Md Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
| | - Md Sohel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
- Department of Biochemistry and Molecular Biology, Primeasia University, Dhaka, Bangladesh
| | - Tayeba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
| | - Md Imran Hasan
- Department of Computer Science and Engineering, Islamic University, Kushtia, 7003, Bangladesh
| | - Md Sharif Khan
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
| | - K M Kaderi Kibria
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
| | - S M Hasan Mahmud
- Department of Computer Science, Faculty of Science and Technology, American International University-Bangladesh, Dhaka, Bangladesh
| | - Md Habibur Rahman
- Department of Computer Science and Engineering, Islamic University, Kushtia, 7003, Bangladesh
- Center for Advanced Bioinformatics and Artificial Intelligent Research, Islamic University, Kushtia, 7003, Bangladesh
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17
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Naz A, Asif S, Alwutayd KM, Sarfaraz S, Abbasi SW, Abbasi A, Alenazi AM, Hasan ME. Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach. Molecules 2023; 28:molecules28072989. [PMID: 37049752 PMCID: PMC10096053 DOI: 10.3390/molecules28072989] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/16/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of −9.7, −9.6, and −9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.
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Affiliation(s)
- Aliza Naz
- National Center for Bioinformatics, Quaid-i-Azam University, Islamabad 45320, Pakistan
- Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad 44000, Pakistan
| | - Sumbul Asif
- Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad 44000, Pakistan
- School of Interdisciplinary Engineering and Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Khairiah Mubarak Alwutayd
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Sara Sarfaraz
- Department of Bioinformatics, Kohsar University Murree, Murree 47150, Pakistan
- Correspondence:
| | - Sumra Wajid Abbasi
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi 46000, Pakistan
| | - Asim Abbasi
- Department of Environmental Sciences, Kohsar University Murree, Murree 47150, Pakistan
| | - Abdulkareem M. Alenazi
- Pediatric Senior Registrar, King Salman Armed Forces Hospital in Northwestern Region (KSAFH), Tabuk 47512, Saudi Arabia
| | - Mohamed E. Hasan
- Bioinformatic Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City 32897, Egypt
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18
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Roy A, Sarkar A, Nayak D, Das S. Ultradiluted SARS-CoV-2 Spike Protein mitigates hyperinflammation in lung via ferritin and MMP-9 regulation in BALB/c mice. Virus Res 2023; 329:199091. [PMID: 36918101 PMCID: PMC10015450 DOI: 10.1016/j.virusres.2023.199091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/16/2023]
Abstract
AIM This study investigated the prophylactic and therapeutic role of ultradiluted preparation of the Delta variant of SARS-CoV-2 recombinant spike (S) protein during S antigen-induced inflammatory process of disease progression along with the probable mechanism of action. MAIN METHODS Ultradiluted S protein (UDSP) was prepared and administered orally to adult BALB/c mice before and after administration of S antigen intranasally. After an observation period of 72 h, animals were sacrificed and expression level of ferritin was assayed through ELISA. The genetic expressions of cytokines, IL-6, IL-10, IL-1β, TNFα, IL-17, MMP-9, TIMP-1, ferritin light and heavy chains, and mitochondrial ferritin from lung tissues were investigated through RT-PCR. Formalin-fixed lung tissue sections were stained with hematoxylin and eosin to observe the degree of pathological changes. The activity of MMP-9 in lung tissues was investigated through gelatin zymography and immunofluorescence of MMP-9 in lung tissue sections was performed to revalidate the finding from gelatin zymography. Systems biology approach was used to elucidate a probable pathway where UDSP attenuated the inflammation through the regulation of pro- and anti-inflammatory cytokines. KEY FINDINGS UDSP attenuated the S antigen-induced hyperinflammation in the lung by regulating pro- and anti-inflammatory cytokines, calming cytokine storm, reducing ferritin level both in transcriptional and translational levels, and restoring critical ratio of MMP-9: TIMP-1. SIGNIFICANCE Our findings suggest a probable pathway by which UDSP might have attenuated inflammation through the regulation of cytokines, receptors, and other molecules. This proclaims UDSP as a promising antiviral agent in the treatment of COVID-19-induced immunopathogenesis.
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Affiliation(s)
- Anirban Roy
- Virology Laboratory, DAC Regional Research Institute, Kolkata, West Bengal 700035, India
| | - Avipsha Sarkar
- Virology Laboratory, DAC Regional Research Institute, Kolkata, West Bengal 700035, India
| | - Debadatta Nayak
- CCRH, Institutional Area, Janakpuri, New Delhi, Delhi 110058, India
| | - Satadal Das
- Virology Laboratory, DAC Regional Research Institute, Kolkata, West Bengal 700035, India.
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19
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Dogra P, Schiavone C, Wang Z, Ruiz-Ramírez J, Caserta S, Staquicini DI, Markosian C, Wang J, Sostman HD, Pasqualini R, Arap W, Cristini V. A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2022.09.14.22279959. [PMID: 36415468 PMCID: PMC9681049 DOI: 10.1101/2022.09.14.22279959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
While the development of different vaccines has slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections continues to fuel the pandemic. As a strategy to secure at least partial protection, with a single dose of a given COVID-19 vaccine to maximum possible fraction of the population, delayed administration of subsequent doses (or boosters) has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may jeopardize the attainment of herd immunity due to intermittent lapses in protection. Optimizing vaccine dosing schedules could thus make the difference between periodic occurrence of breakthrough infections or effective control of the pandemic. To this end, we have developed a mechanistic mathematical model of adaptive immune response to vaccines and demonstrated its applicability to COVID-19 mRNA vaccines as a proof-of-concept for future outbreaks. The model was thoroughly calibrated against multiple clinical datasets involving immune response to SARS-CoV-2 infection and mRNA vaccines in healthy and immunocompromised subjects (cancer patients undergoing therapy); the model showed robust clinical validation by accurately predicting neutralizing antibody kinetics, a correlate of vaccine-induced protection, in response to multiple doses of mRNA vaccines. Importantly, we estimated population vulnerability to breakthrough infections and predicted tailored vaccination dosing schedules to maximize protection and thus minimize breakthrough infections, based on the immune status of a sub-population. We have identified a critical waiting window for cancer patients (or, immunocompromised subjects) to allow recovery of the immune system (particularly CD4+ T-cells) for effective differentiation of B-cells to produce neutralizing antibodies and thus achieve optimal vaccine efficacy against variants of concern, especially between the first and second doses. Also, we have obtained optimized dosing schedules for subsequent doses in healthy and immunocompromised subjects, which vary from the CDC-recommended schedules, to minimize breakthrough infections. The developed modeling tool is based on generalized adaptive immune response to antigens and can thus be leveraged to guide vaccine dosing schedules during future outbreaks.
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Affiliation(s)
- Prashant Dogra
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA
| | - Carmine Schiavone
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples Federico II, Naples, Italy
| | - Zhihui Wang
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA
- Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA
| | - Javier Ruiz-Ramírez
- Centro de Ciencias de la Salud, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Sergio Caserta
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples Federico II, Naples, Italy
- CEINGE Advanced Biotechnologies, Naples, Italy
| | - Daniela I. Staquicini
- Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Christopher Markosian
- Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Jin Wang
- Immunobiology and Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - H. Dirk Sostman
- Weill Cornell Medicine, New York, NY, USA
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Academic Institute, Houston, TX, USA
| | - Renata Pasqualini
- Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Wadih Arap
- Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Vittorio Cristini
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA
- Department of Imaging Physics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Physiology, Biophysics, and Systems Biology Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA
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20
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Khreefa Z, Barbier MT, Koksal AR, Love G, Del Valle L. Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas. Cells 2023; 12:cells12020262. [PMID: 36672197 PMCID: PMC9856332 DOI: 10.3390/cells12020262] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/30/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal-oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.
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Affiliation(s)
- Zaid Khreefa
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
| | - Mallory T. Barbier
- Louisiana Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Gordon Love
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
| | - Luis Del Valle
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
- Louisiana Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
- Correspondence:
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21
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Herscu P, Talele G, Vaidya S, Shah R. Safety and Evaluation of the Immune Response of Coronavirus Nosode (BiosimCovex) in Healthy Volunteers: A Preliminary Study Extending the Homeopathic Pathogenetic Trial. MEDICINES (BASEL, SWITZERLAND) 2022; 10:8. [PMID: 36662492 PMCID: PMC9865918 DOI: 10.3390/medicines10010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/21/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023]
Abstract
Objectives: Regulatory clinical Phase I studies are aimed at establishing the human safety of an active pharmaceutical agent to be later marketed as a drug. Since homeopathic medicines are prepared by a potentizing method using alcohol, past a certain dilution, their toxicity/infectivity is assumed to be unlikely. We aimed to develop a bridge study between homeopathic pathogenetic trials and clinical trials. The primary purpose was to evaluate the safety of a nosode, developed from clinical samples of a COVID-19 patient. The secondary objectives were to explore whether a nosode developed for a specific clinical purpose, such as use during an epidemic, may elicit laboratory signals worthy of further exploration. Methods: An open-label study was designed to evaluate the safety and immune response of the Coronavirus nosode BiosimCovex, given orally on three consecutive days to ten healthy volunteers. Clinical examinations, laboratory safety and immune parameters were established. Interferon-gamma, Interleukin-6, and CD 4 were measured. (CTRI registration number: CTRI/2020/05/025496). Results: No serious/fatal adverse events were reported. Laboratory tests to measure safety were unchanged. Three subjects showed elevated Interleukin-6 (IL-6) on day 17 in comparison to the baseline, and ten subjects showed elevated IL-6 on day 34. A significant difference between IL-6 observations, calculated by repeated measures ANOVA, was found to be highly significant. On day 60, the IL-6 values of nine subjects were found to return to normal. Corresponding CD4 cell elevation was observed on day 60, when compared to day 34. Conclusions: HPT may potentially extend into physiological changes with regards to immune response and should encourage future studies.
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Affiliation(s)
- Paul Herscu
- Herscu Laboratory, Research Division, 356 Middle Street, Amherst, MA 01002, USA
| | - Gitanjali Talele
- Life Force Foundation Trust, 411 Krushal Commercial Complex, Chembur, Mumbai 400089, Maharashtra, India
| | - Shashikant Vaidya
- Assistant Director and HOD Microbiology Department, Haffkine Institute for Training Research and Testing, Acharya Dhonde Marg, Parel Village, Parmanand Wadi, Parel, Mumbai 400012, Maharashtra, India
| | - Rajesh Shah
- Life Force Foundation Trust, 411 Krushal Commercial Complex, Chembur, Mumbai 400089, Maharashtra, India
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22
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Skakun O, Fedorov S, Seredyuk N, Verbovska O. Prognostic Value of Serum Interleukin-6 Level in Hypertensive Patients with COVID-19-Associated Pneumonia. GALICIAN MEDICAL JOURNAL 2022. [DOI: 10.21802/gmj.2022.4.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background. An interleukin-6 (IL-6) is a proinflammatory cytokine which plays an important role in COVID-19-associated hyperinflammation.
Aim. This study aimed to assess the predictive ability of serum IL-6 levels for the development of severe/critical clinical conditions, a hypoxemic state requiring supplemental oxygen, and lethal outcomes in patients with COVID-19-associated pneumonia and arterial hypertension (AH).
Materials and Methods. One hundred and thirty-five unvaccinated patients hospitalized for COVID-19-associated pneumonia were enrolled in the study. AH was diagnosed in 78.5% of cases. Pneumonia was confirmed radiologically. SARS-COV-2 as an etiological factor was confirmed by either PCR or ELISA. In addition to conventional laboratory tests, IL-6, ferritin, and soluble interleukin-2 levels were measured.
Results. Among AH patients, the median levels of IL-6 were higher in non-survivors (95.1 [37.8 - 158.8] pg/mL) as compared to survivors (39.5 [13.6 - 81.1] pg/mL) (p=0.04). Among AH patients, the median serum level of IL-6 was 98.3 [37.8 - 158.8] pg/mL in critically ill patients, 41.7 [11.8 - 83.4] pg/mL in severely ill patients, 37.8 [13.6 - 74.4] pg/mL in moderately ill patients (p=0.051). The median serum level of IL-6 was lower at the time of discharge (6.5 [2.0 - 21.5] pg/mL) as compared to that on admission (43.2 [16.1 - 92.0] pg/mL) (p< 0.001). IL-6 level failed to predict severe/critical condition (AUC=0.59, p=0.13) and the need for supplemental oxygen (AUC=0.61, p=0.06); however, it might be used for the prediction of the lethal outcome (AUC=0.69, p=0.03). The cut-off value of IL-6 level for lethal outcome prediction of 91.0 pg/mL showed a sensitivity of 58.3% and a specificity of 78.7%. Patients with IL-6 levels > 91.0 pg/mL on admission had higher odds of lethal outcomes (OR = 4.87 [1.40 - 16.92], p=0.01).
Conclusions. Serum IL-6 level on admission did not show significant predictive ability for severe/critical conditions and hypoxemic states requiring supplemental oxygen in AH patients. However, serum IL-6 levels on admission were higher in non-survivors and might be used for the prediction of lethal outcomes with a cut-off value of 91.0 pg/mL in AH patients.
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23
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Mosadegh M, Khalkhali A, Erfani Y, Nezamdoost M. The effect of Nutrition Bio-shield superfood (NBS) on disease severity and laboratory biomarkers in patients with COVID-19: A randomized clinical trial. Microb Pathog 2022; 172:105792. [PMID: 36165862 PMCID: PMC9482870 DOI: 10.1016/j.micpath.2022.105792] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 07/20/2022] [Accepted: 09/14/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND Nutrition Bio-shield Superfood (NBS) is an organic and viable herbal supplement that could improve the function of the immune system. The present study aims to determine the effect of NBS on disease severity and laboratory biomarkers in patients with COVID-19. METHODS This current study was a randomized, comparative, parallel two-arm and single-blind clinical trial study performed in Tehran, Iran. In total, 70 patients with COVID-19 were included in the present study and assigned to two groups including 1) intervention group (n = 35) and 2) control group (n = 35). All patients included in the intervention group received 4.5 gr daily rate of NBS superfood, three times the daily rate of 1.5 gr for 14 days. In contrast, patients included in the control group received a placebo three times a day for 14 days. The measurement of laboratory parameters including CRP, ESR, D-Dimer, LDH, CPK, SGOT, SGPT, ALP, FBG, WBC count, PLT, and lymphocyte count was performed using standard kits and methods. Moreover, all serum samples were tested to determine the levels of IL-6 and TNF-ɑ using specific commercially available ELISA kits according to the instructions of the manufacturer. RESULTS A significant decrease in the mean serum level of several variables including CRP (p < 0.001), ESR (p < 0.001), D- Dimer (p = 0.001), LDH (p < 0.001), SGOT (p = 0.002), SGPT (p = 0.019), ALP (p < 0.001), WBC count (p < 0.001), body temperature (p = 0.013), IL-6 (p < 0.001), and TNF-α (p < 0.001) was seen 14 days after intervention from baseline in the intervention group than control group. In contrast, in the intervention group, the significant increase from baseline of lymphocyte percentage (p < 0.001) and oxygen saturation (p < 0.001) was seen 14 days after receiving NBS superfood than the control group. CONCLUSION Results showed that the use of NBS superfood had various beneficial effects on COVID-19 disease severity. These results suggest that NBS superfood can be used as an effective natural supplement in the treatment process of COVID-19 disease.
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Affiliation(s)
- Mehrdad Mosadegh
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Aref Khalkhali
- Department of Science, Faculty of Biology, Islamic Azad University, Mashhad, Iran
| | - Yousef Erfani
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Manije Nezamdoost
- Department of Internal Medicine, Division of Infectious Disease, Farabi Hospital, Social Security Organization, Mashhad, Iran
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Pitamberwale A, Mahmood T, Ansari AK, Ansari SA, Limgaokar K, Singh L, Karki G. Biochemical Parameters as Prognostic Markers in Severely Ill COVID-19 Patients. Cureus 2022; 14:e28594. [PMID: 36185918 PMCID: PMC9521622 DOI: 10.7759/cureus.28594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
Background Prognostication plays a pivotal role in critical care medicine. Its importance is indisputable in the management of coronavirus disease 2019 (COVID-19), as the presentation of this disease may vary from docile, self-limiting symptoms to lethal conditions. Amid the COVID-19 pandemic, much emphasis was initially placed on molecular and serological testing. However, it was realized later that routine laboratory tests also provide key information in terms of the severity of the disease and thus could be used to predict the outcome of these patients. Methodology The aim of our study was to evaluate the biochemical parameters as prognostic markers in severely ill COVID-19 patients. We carried out a retrospective, case-control study. The study population was comprised of all severely ill COVID-19 patients admitted between October 2020 and January 2021 at our level 3 COVID hospital. Cases were defined as the patients who expired despite treatment and all resuscitative measures as per the standard operating procedures (SOPs) of our COVID intensive care unit (ICU) while controls were defined as the patients that were transferred out of the COVID ICU for further recovery. The detailed history, findings of physical examination, vitals recorded by point of care testing (POCT) devices at our ICU, clinical diagnosis, and the results of the biochemical analysis were recorded in a specially designed pro forma. The biochemical parameters recorded at the time of admission were compared between the groups of controls and cases in order to evaluate their role as predictors of mortality using appropriate statistical methods. P-values less than 0.05 were considered statistically significant. For all the parameters that showed a statistically significant difference, receiver operating characteristics (ROC) analysis was done to assess the utility of biochemical parameters as predictors of mortality or survival. Areas under the curve (AUCs) of 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, and >0.9 were considered acceptable, fair, good, and excellent for discrimination, respectively. Results Of the 178 severely ill COVID-19 patients enrolled in the study, 86 were controls and 92 were cases (52% mortality). Serum urea (p<0.0001), creatinine (p=0.0019), aspartate transaminase (AST) (p=0.0104), lactate dehydrogenase (LDH) (p=0.0001), procalcitonin (PCT) (p=0.0344), and interleukin 6 (IL-6) (p=0.0311) levels were significantly higher (p<0.05), while total protein (p=0.0086), albumin (p<0.0001), and indirect bilirubin (p=0.0147) levels were significantly lower (p<0.05) in cases as compared to controls. The difference was statistically insignificant (p>0.05) for serum sodium, potassium, total and direct bilirubin, globulin, alanine transaminase (ALT), alkaline phosphatase (ALP), D-dimer, and ferritin. On ROC analysis, urea was fair (AUC=0.721), creatinine (AUC=0.698) and IL-6 (AUC=0.698) were acceptable predictors of mortality, while albumin (AUC=0.698) was an acceptable predictor of survival in severely ill COVID-19 patients during their intensive care stay. Conclusion Understanding the pathophysiological changes associated with the severity of COVID-19 in terms of an alteration of biochemical parameters is a pressing priority. Our study highlights the importance of routine laboratory tests in predicting outcomes in severely ill COVID-19 patients.
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Piretto E, Selvaggio G, Bragantini D, Domenici E, Marchetti L. A novel logical model of COVID-19 intracellular infection to support therapies development. PLoS Comput Biol 2022; 18:e1010443. [PMID: 36037223 PMCID: PMC9462742 DOI: 10.1371/journal.pcbi.1010443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 09/09/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022] Open
Abstract
In this paper, a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection has been developed to study various drug treatments (single or in combination), in different illness scenarios, providing insights into their mechanisms of action. Drug simulations suggest that the effects of single drugs are limited, or depending on the scenario counterproductive, whereas better results appear combining different treatments. Specifically, the combination of the anti-inflammatory Baricitinib and the anti-viral Remdesivir showed significant benefits while a stronger efficacy emerged from the triple combination of Baricitinib, Remdesivir, and the corticosteroid Dexamethasone. Together with a sensitivity analysis, we performed an analysis of the mechanisms of the drugs to reveal their impact on molecular pathways. The paper introduces a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection. The aim of the model is to study, in a qualitative but comprehensive way, the cellular mechanisms developed during the virus infection with the principal focus on drug treatments. The model is able to reproduce various illness scenarios: from the early infection stages to the late illness stages characterized by strong immune reaction usually evolving in the so-called cytokine storm. Different drug effects have been tested singularly and in combination treatments. Computational sensitivity analysis was performed on the model along with the analysis of the mechanisms of the drugs to reveal their impact on molecular pathways. The results show that the effect of single drugs may be limited or counterproductive, depending on the illness stage. The highest predicted efficacy is obtained by combining three different treatments: the anti-inflammatory Baricitinib, the anti-viral Remdesivir and the corticosteroid Dexamethasone. This triple combination therapy has been analyzed not only in terms of global cellular effect but also in function of the involved internal pathways, suggesting the rational mechanisms for its successfulness.
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Affiliation(s)
| | - Gianluca Selvaggio
- Fondazione The Microsoft Research—University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Trento, Italy
| | - Damiano Bragantini
- Infectious Diseases Unit, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Enrico Domenici
- Fondazione The Microsoft Research—University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Trento, Italy
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Povo, Trento, Italy
| | - Luca Marchetti
- Fondazione The Microsoft Research—University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Trento, Italy
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Povo, Trento, Italy
- * E-mail: ;
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Wang Z, Cryar A, Lemke O, Tober-Lau P, Ludwig D, Helbig ET, Hippenstiel S, Sander LE, Blake D, Lane CS, Sayers RL, Mueller C, Zeiser J, Townsend S, Demichev V, Mülleder M, Kurth F, Sirka E, Hartl J, Ralser M. A multiplex protein panel assay for severity prediction and outcome prognosis in patients with COVID-19: An observational multi-cohort study. EClinicalMedicine 2022; 49:101495. [PMID: 35702332 PMCID: PMC9181834 DOI: 10.1016/j.eclinm.2022.101495] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022] Open
Abstract
Background Global healthcare systems continue to be challenged by the COVID-19 pandemic, and there is a need for clinical assays that can help optimise resource allocation, support treatment decisions, and accelerate the development and evaluation of new therapies. Methods We developed a multiplexed proteomics assay for determining disease severity and prognosis in COVID-19. The assay quantifies up to 50 peptides, derived from 30 known and newly introduced COVID-19-related protein markers, in a single measurement using routine-lab compatible analytical flow rate liquid chromatography and multiple reaction monitoring (LC-MRM). We conducted two observational studies in patients with COVID-19 hospitalised at Charité - Universitätsmedizin Berlin, Germany before (from March 1 to 26, 2020, n=30) and after (from April 4 to November 19, 2020, n=164) dexamethasone became standard of care. The study is registered in the German and the WHO International Clinical Trials Registry (DRKS00021688). Findings The assay produces reproducible (median inter-batch CV of 10.9%) absolute quantification of 47 peptides with high sensitivity (median LLOQ of 143 ng/ml) and accuracy (median 96.8%). In both studies, the assay reproducibly captured hallmarks of COVID-19 infection and severity, as it distinguished healthy individuals, mild, moderate, and severe COVID-19. In the post-dexamethasone cohort, the assay predicted survival with an accuracy of 0.83 (108/130), and death with an accuracy of 0.76 (26/34) in the median 2.5 weeks before the outcome, thereby outperforming compound clinical risk assessments such as SOFA, APACHE II, and ABCS scores. Interpretation Disease severity and clinical outcomes of patients with COVID-19 can be stratified and predicted by the routine-applicable panel assay that combines known and novel COVID-19 biomarkers. The prognostic value of this assay should be prospectively assessed in larger patient cohorts for future support of clinical decisions, including evaluation of sample flow in routine setting. The possibility to objectively classify COVID-19 severity can be helpful for monitoring of novel therapies, especially in early clinical trials. Funding This research was funded in part by the European Research Council (ERC) under grant agreement ERC-SyG-2020 951475 (to M.R) and by the Wellcome Trust (IA 200829/Z/16/Z to M.R.). The work was further supported by the Ministry of Education and Research (BMBF) as part of the National Research Node 'Mass Spectrometry in Systems Medicine (MSCoresys)', under grant agreements 031L0220 and 161L0221. J.H. was supported by a Swiss National Science Foundation (SNSF) Postdoc Mobility fellowship (project number 191052). This study was further supported by the BMBF grant NaFoUniMedCOVID-19 - NUM-NAPKON, FKZ: 01KX2021. The study was co-funded by the UK's innovation agency, Innovate UK, under project numbers 75594 and 56328.
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Affiliation(s)
- Ziyue Wang
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Adam Cryar
- Inoviv, Mappin House, 4 Winsley St, London, United Kingdom
| | - Oliver Lemke
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Pinkus Tober-Lau
- Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Daniela Ludwig
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Elisa Theresa Helbig
- Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Stefan Hippenstiel
- Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Leif-Erik Sander
- Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at the Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | | | | | - Christoph Mueller
- Agilent Technologies Sales & Services GmbH & Co. KG, Waldbronn, Germany
| | - Johannes Zeiser
- Agilent Technologies Sales & Services GmbH & Co. KG, Waldbronn, Germany
| | - StJohn Townsend
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Vadim Demichev
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Michael Mülleder
- Core Facility – High-Throughput Mass Spectrometry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Florian Kurth
- Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, and Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ernestas Sirka
- Inoviv, Mappin House, 4 Winsley St, London, United Kingdom
| | - Johannes Hartl
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
| | - Markus Ralser
- Department of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Am Chariteplatz 1, 10117 Berlin, Germany
- The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
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Inflammatory and thrombotic parameters associated with the COVID-19 course in Poland (SARSTer study). Adv Med Sci 2022; 67:291-297. [PMID: 35932632 PMCID: PMC9296792 DOI: 10.1016/j.advms.2022.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/16/2022] [Accepted: 07/14/2022] [Indexed: 11/25/2022]
Abstract
Purpose The aim of the study was to assess the coagulation and inflammatory markers connected with severe course of COVID-19 and no clinical improvement. Material and methods The study population included 2590 adult patients, diagnosed with COVID-19, selected from the SARSTer national database - an ongoing project led by the Polish Association of Epidemiologists and Infectiologists and supported by the Medical Research Agency. Clinical and laboratory parameters, such as C-reactive protein (CRP), white blood cells (WBCs), neutrophil and lymphocyte count, procalcitonin, ferritin, interleukin-6 (IL-6), D-dimer concentration and platelet (PLT) count were analyzed before and after treatment (remdesivir, tocilizumab, dexamethasone, anticoagulants). Results Significant differences between patients with mild and severe course of the disease were observed in all examined parameters before treatment (p < 0.05). After treatment only ferritin concentration did not differ significantly. In patients with pulmonary embolism, CRP concentration, neutrophil count, D-dimer and IL-6 concentration were significantly higher than in patients without embolism (p < 0.05). The significant differences between the groups with and without fatal outcome were observed within all analyzed parameters. Significant differences in all examined parameters before treatment were observed between patients with and without clinical improvement (p < 0.05). Multivariate logistic regression showed that no clinical improvement was associated with: IL-6>100 pg/ml (OR-2.14), D-dimer concentration over 1000 ng/ml (OR-1.62) and PLT count below 150,000/μl (OR-1.57). Conclusions Severe course of the disease is associated with lower PLT and lymphocyte count, higher D-dimer, CRP, neutrophil count and IL-6 concentration. The best predictors of no clinical improvement in COVID-19 are: IL-6>100 pg/ml, D-dimer>1000 ng/ml and PLT<150,000/μl.
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Histopathological and molecular links of COVID-19 with novel clinical manifestations for the management of coronavirus-like complications. Inflammopharmacology 2022; 30:1219-1257. [PMID: 35637319 PMCID: PMC9150634 DOI: 10.1007/s10787-022-00999-9] [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: 03/31/2022] [Accepted: 04/12/2022] [Indexed: 01/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) causes transmissible viral illness of the respiratory tract prompted by the SARS-CoV-2 virus. COVID-19 is one of the worst global pandemics affecting a large population worldwide and causing catastrophic loss of life. Patients having pre-existing chronic disorders are more susceptible to contracting this viral infection. This pandemic virus is known to cause notable respiratory pathology. Besides, it can also cause extra-pulmonary manifestations. Multiple extra-pulmonary tissues express the SARS-CoV-2 entry receptor, hence causing direct viral tissue damage. This insightful review gives a brief description of the impact of coronavirus on the pulmonary system, extra-pulmonary systems, histopathology, multiorgan consequences, the possible mechanisms associated with the disease, and various potential therapeutic approaches to tackle the manifestations.
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Atallah J, Archambault D, Randall JD, Shepro A, Styskal LE, Glenn DR, Connolly CB, Katsis K, Gallagher K, Ghebremichael M, Mansour MK. Rapid Quantum Magnetic IL-6 Point-of-Care Assay in Patients Hospitalized with COVID-19. Diagnostics (Basel) 2022; 12:1164. [PMID: 35626318 PMCID: PMC9139897 DOI: 10.3390/diagnostics12051164] [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: 03/22/2022] [Revised: 04/28/2022] [Accepted: 05/05/2022] [Indexed: 11/21/2022] Open
Abstract
Interleukin-6 (IL-6) has been linked to several life-threatening disease processes. Developing a point-of-care testing platform for the immediate and accurate detection of IL-6 concentrations could present a valuable tool for improving clinical management in patients with IL-6-mediated diseases. Drawing on an available biobank of samples from 35 patients hospitalized with COVID-19, a novel quantum-magnetic sensing platform is used to determine plasma IL-6 concentrations. A strong correlation was observed between IL-6 levels measured by QDTI10x and the Luminex assay (r = 0.70, p-value < 0.001) and between QDTI80x and Luminex (r = 0.82, p-value < 0.001). To validate the non-inferiority of QDTI to Luminex in terms of the accuracy of IL-6 measurement, two clinical parameters—the need for intensive care unit admission and the need for mechanical intubation—were chosen. IL-6 concentrations measured by the two assays were compared with respect to these clinical outcomes. Results demonstrated a comparative predictive performance between the two assays with a significant correlation coefficient. Conclusion: In short, the QDTI assay holds promise for implementation as a potential tool for rapid clinical decision in patients with IL-6-mediated diseases. It could also reduce healthcare costs and enable the development of future various biomolecule point-of-care tests for different clinical scenarios.
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Affiliation(s)
- Johnny Atallah
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; (J.A.); (D.A.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
| | - Dakota Archambault
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; (J.A.); (D.A.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
| | - Jeffrey D. Randall
- Quantum Diamond Technologies Inc., Somerville, MA 02143, USA; (J.D.R.); (A.S.); (L.E.S.); (D.R.G.); (C.B.C.)
| | - Adam Shepro
- Quantum Diamond Technologies Inc., Somerville, MA 02143, USA; (J.D.R.); (A.S.); (L.E.S.); (D.R.G.); (C.B.C.)
| | - Lauren E. Styskal
- Quantum Diamond Technologies Inc., Somerville, MA 02143, USA; (J.D.R.); (A.S.); (L.E.S.); (D.R.G.); (C.B.C.)
| | - David R. Glenn
- Quantum Diamond Technologies Inc., Somerville, MA 02143, USA; (J.D.R.); (A.S.); (L.E.S.); (D.R.G.); (C.B.C.)
| | - Colin B. Connolly
- Quantum Diamond Technologies Inc., Somerville, MA 02143, USA; (J.D.R.); (A.S.); (L.E.S.); (D.R.G.); (C.B.C.)
| | - Katelin Katsis
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
| | - Kathleen Gallagher
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
| | - Musie Ghebremichael
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02138, USA
| | - Michael K. Mansour
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; (J.A.); (D.A.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (K.K.); (K.G.); (M.G.)
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Tandara L, Filipi P, Supe Domic D, Kresic B, Ivcic I, Stojanovic Stipic S, Rubic Z, Tandara M. Laboratory medicine in pandemic of COVID-19. Biochem Med (Zagreb) 2022; 32:020501. [PMID: 35464749 PMCID: PMC8996317 DOI: 10.11613/bm.2022.020501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/01/2022] [Indexed: 11/01/2022] Open
Abstract
After the outbreak in China in the year 2019, severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) quickly spread around the world causing a protracted pandemic. Approximately one-third of infections appear to be asymptomatic. Symptomatic disease is characterized primarily by symptoms of respiratory tract infection of varying severity. But Coronavirus Disease 2019 (COVID-19) is much more than an acute respiratory disease because SARS-CoV-2 affects many organs inducing a vast number of symptoms such as cardiovascular, neurological, gastrointestinal, dermatological, with numerous complications. Short and long-term effects of infection, severe ones, and especially mild forms of the disease which affect a huge number of patients need to be further investigated. Laboratory medicine has a crucial role in early diagnosis of the disease, recognition of the patients who need hospital care, and close monitoring of hospitalized patients to timely identify associated clinical complications as well as follow-up of patients with long-term COVID-19.
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Affiliation(s)
- Leida Tandara
- Department of Medical Laboratory Diagnostic, University Hospital Split, Split, Croatia
- University of Split School of Medicine, Split, Croatia
- Corresponding author:
| | - Petra Filipi
- Department of Medical Laboratory Diagnostic, University Hospital Split, Split, Croatia
| | - Daniela Supe Domic
- Department of Medical Laboratory Diagnostic, University Hospital Split, Split, Croatia
- University Department of Health Studies, University of Split, Split, Croatia
| | - Branka Kresic
- Department of Medical Laboratory Diagnostic, University Hospital Split, Split, Croatia
| | - Ivo Ivcic
- University of Split School of Medicine, Split, Croatia
- Clinic for Infectious Diseases, University Hospital Split, Split, Croatia
| | - Sanda Stojanovic Stipic
- University of Split School of Medicine, Split, Croatia
- Department of Anaesthesiology and Intensive Care, University Hospital Split, Split, Croatia
| | - Zana Rubic
- University of Split School of Medicine, Split, Croatia
- Department of Clinical Microbiology, University Hospital Split, Split, Croatia
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Kocherlakota C, Nagaraju B, Arjun N, Srinath A, Kothapalli KSD, Brenna JT. Inhalation of nebulized omega-3 fatty acids mitigate LPS-induced acute lung inflammation in rats: Implications for treatment of COPD and COVID-19. Prostaglandins Leukot Essent Fatty Acids 2022; 179:102426. [PMID: 35381532 PMCID: PMC8964507 DOI: 10.1016/j.plefa.2022.102426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 01/08/2023]
Abstract
Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour post-injection, rats received nebulized treatments consisting of egg lecithin emulsified O3, Budesonide and Montelukast, and blends of O3 and Melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n = 3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3FA groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress such as COVID-19.
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Affiliation(s)
| | - Banda Nagaraju
- Leiutis Pharmaceuticals LLP, Plot No. 23, TIE 1st Phase, Balanagar, Hyderabad, Telangana 500037, India
| | - Narala Arjun
- Leiutis Pharmaceuticals LLP, Plot No. 23, TIE 1st Phase, Balanagar, Hyderabad, Telangana 500037, India
| | - Akula Srinath
- Leiutis Pharmaceuticals LLP, Plot No. 23, TIE 1st Phase, Balanagar, Hyderabad, Telangana 500037, India
| | - Kumar S D Kothapalli
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, United States.
| | - J Thomas Brenna
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, United States.
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32
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Xu M, Li N, Fan X, Zhou Y, Bi S, Shen A, Wang B. Differential Effects of Toll-Like Receptor Signaling on the Activation of Immune Responses in the Upper Respiratory Tract. Microbiol Spectr 2022; 10:e0114421. [PMID: 35196817 PMCID: PMC8865572 DOI: 10.1128/spectrum.01144-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/28/2022] [Indexed: 11/20/2022] Open
Abstract
Vaccination through the upper respiratory tract (URT) is highly effective for the prevention of respiratory infectious diseases. Toll-like receptor (TLR)-based adjuvants are immunostimulatory and considered potential adjuvant candidates. However, the patterns of immune response to different TLRs at the URT have not been revealed. In this study, SPF mice were preexposed to TLR agonists intranasally to simulate the status of humans. Inflammatory response to TLR agonists and TLR signal-mediated adaptive immune responses were analyzed. The results revealed that similar to human tonsils, inflammatory response to stimulation with TLR4 or TLR2 agonist was attenuated in agonist-exposed mice but not in mice without this exposure. In contrast, TLR9 or TLR3 agonist preexposure did not affect the inflammatory response to restimulation by matching agonists. For the adaptive immune response, after agonist preexposure the antibody response to antigens adjuvanted with TLR4 or TLR2 agonist was substantially restricted, whereas, both antibody and T cell responses to antigens adjuvanted with TLR9 or TLR3 agonist were activated as robustly as in mice without agonist exposure. Moreover, we demonstrate that the mechanisms underlying the differential activation of TLRs are regulated at the level of TLR expression in innate and adaptive immune cells. These results indicate that TLRs on the cell surface (TLR4 and 2) and in the endolysosomal compartments (TLR9 and 3) display distinct immune response patterns. The findings provide important information for the use of TLR agonists as mucosal adjuvants and enhance our understanding of immune responses to bacterial and viral infections in the respiratory mucosa. IMPORTANCE Agonists of TLRs are potential adjuvant candidates for mucosal vaccination. We demonstrated that the TLR-mediated inflammatory and antibody responses in the URT of SPF mice exposed to extracellular TLR agonists were substantially restricted. In contrast, inflammatory and adaptive immune responses, including B and T cell activation, were not desensitized in mice exposed to intracellular TLR agonists. The distinct responsive patterns of extra and intracellular TLRs regulated at TLR expression in immune cells. The results indicated that TLRs differentially impact the innate and adaptive immune response in the URT, which contributes to the selection of TLR-based mucosal adjuvants and helps understand the difference between the immune response in bacterial and viral infections.
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Affiliation(s)
- Meiyi Xu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Ning Li
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Xin Fan
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Ya Zhou
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Shuai Bi
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Adong Shen
- Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Beijing, China
| | - Beinan Wang
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
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33
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Lasserre P, Balansethupathy B, Vezza VJ, Butterworth A, Macdonald A, Blair EO, McAteer L, Hannah S, Ward AC, Hoskisson PA, Longmuir A, Setford S, Farmer ECW, Murphy ME, Flynn H, Corrigan DK. SARS-CoV-2 Aptasensors Based on Electrochemical Impedance Spectroscopy and Low-Cost Gold Electrode Substrates. Anal Chem 2022; 94:2126-2133. [PMID: 35043638 PMCID: PMC8790822 DOI: 10.1021/acs.analchem.1c04456] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/24/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 diagnostic practices broadly involve either quantitative polymerase chain reaction (qPCR)-based nucleic amplification of viral sequences or antigen-based tests such as lateral flow assays (LFAs). Reverse transcriptase-qPCR can detect viral RNA and is the gold standard for sensitivity. However, the technique is time-consuming and requires expensive laboratory infrastructure and trained staff. LFAs are lower in cost and near real time, and because they are antigen-based, they have the potential to provide a more accurate indication of a disease state. However, LFAs are reported to have low real-world sensitivity and in most cases are only qualitative. Here, an antigen-based electrochemical aptamer sensor is presented, which has the potential to address some of these shortfalls. An aptamer, raised to the SARS-CoV-2 spike protein, was immobilized on a low-cost gold-coated polyester substrate adapted from the blood glucose testing industry. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times as short as 15 min on nasopharyngeal swab samples. This assay can readily be optimized for mass manufacture and is compatible with a low-cost meter.
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Affiliation(s)
- Perrine Lasserre
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | | | - Vincent J. Vezza
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Adrian Butterworth
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Alexander Macdonald
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Ewen O. Blair
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Liam McAteer
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Stuart Hannah
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
| | - Andrew C. Ward
- Department
of Civil and Environmental Engineering, University of Strathclyde, 75 Montrose Street, Glasgow G1 1XJ, U.K.
| | - Paul A. Hoskisson
- Strathclyde
Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
| | - Alistair Longmuir
- LifeScan
Scotland Ltd, Beechwood Park North, Inverness IV2 3ED, U.K.
| | - Steven Setford
- LifeScan
Scotland Ltd, Beechwood Park North, Inverness IV2 3ED, U.K.
| | - Eoghan C. W. Farmer
- NHS GGC,
Department of Microbiology, Glasgow Royal
Infirmary, NEW Lister Building, Glasgow G31 2ER, United Kingdom
| | - Michael E. Murphy
- NHS GGC,
Department of Microbiology, Glasgow Royal
Infirmary, NEW Lister Building, Glasgow G31 2ER, United Kingdom
- School
of Medicine, Dentistry & Nursing, College of Medical Veterinary
& Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
| | - Harriet Flynn
- Aptamer
Group, Suite 2.78−2.91,
Bio Centre, Innovation Way, Heslington, York YO10 5NY, U.K.
- Department
of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral
Street, Glasgow, G1 1XL, United Kingdom
| | - Damion K. Corrigan
- Department
of Biomedical Engineering, University of
Strathclyde, 106 Rottenrow East, Glasgow G4 0NW, U.K.
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34
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Thirumal Kumar D, Shree Devi M, Udhaya Kumar S, Sherlin A, Mathew A, Lakshmipriya M, Sathiyarajeswaran P, Gnanasambandan R, Siva R, Magesh R, George Priya Doss C. Understanding the activating mechanism of the immune system against COVID-19 by Traditional Indian Medicine: Network pharmacology approach. IMMUNOTHERAPEUTICS 2022; 129:275-379. [PMID: 35305722 PMCID: PMC8798878 DOI: 10.1016/bs.apcsb.2021.11.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions are occurring rapidly; it is raising the alarm around the globe. Though vaccines are currently available, the evolution and mutations in the SARS-CoV-2 threaten available vaccines' significance. The drugs are still undergoing clinical trials, and certain medications are approved for “emergency use” or as an “off-label” drug during the pandemic. These drugs have been effective yet accommodating side effects, which also can be lethal. Complementary and alternative medicine is highly demanded since it embraces a holistic approach. Since ancient times, natural products have been used as drugs to treat various diseases in the medical field and are still widely practiced. Medicinal plants contain many active compounds that serve as the key to an effective drug design. The Kabasura kudineer and Nilavembu kudineer are the two most widely approved formulations to treat COVID-19. However, the mechanism of these formulations is not well known. The proposed study used a network pharmacology approach to understand the immune-boosting mechanism by the Kabasura kudineer, Nilavembu kudineer, and JACOM in treating COVID-19. The plants and phytochemical chemical compounds in the Kabasura kudineer, Nilavembu kudineer, and JACOM were obtained from the literature. The Swiss target prediction algorithm was used to predict the targets for these phytochemical compounds. The common genes for the COVID-19 infection and the drug targets were identified. The gene–gene interaction network was constructed to understand the interactions between these common genes and enrichment analyses to determine the biological process, molecular functions, cellular functions, pathways involved, etc. Finally, virtual screening and molecular docking studies were performed to identify the most potential targets and significant phytochemical compounds to treat the COVID-19. The present study identified potential targets as ACE, Cathepsin L, Cathepsin B, Cathepsin K, DPP4, EGFR, HDAC2, IL6, RIPK1, and VEGFA. Similarly, betulinic acid, 5″-(2⁗-Hydroxybenzyl) uvarinol, antofine, (S)-1′-methyloctyl caffeate, (Z)-3-phenyl-2-propenal, 7-oxo-10α-cucurbitadienol, and PLX-4720 collectively to be potential treatment agents for COVID-19.
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35
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Pinheiro T, Cardoso AR, Sousa CEA, Marques AC, Tavares APM, Matos AM, Cruz MT, Moreira FTC, Martins R, Fortunato E, Sales MGF. Paper-Based Biosensors for COVID-19: A Review of Innovative Tools for Controlling the Pandemic. ACS OMEGA 2021; 6:29268-29290. [PMID: 34778604 PMCID: PMC8577188 DOI: 10.1021/acsomega.1c04012] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/18/2021] [Indexed: 05/07/2023]
Abstract
The appearance and quick spread of the new severe acute respiratory syndrome coronavirus disease, COVID-19, brought major societal challenges. Importantly, suitable medical diagnosis procedures and smooth clinical management of the disease are an emergent need, which must be anchored on novel diagnostic methods and devices. Novel molecular diagnostic tools relying on nucleic acid amplification testing have emerged globally and are the current gold standard in COVID-19 diagnosis. However, the need for widespread testing methodologies for fast, effective testing in multiple epidemiological scenarios remains a crucial step in the fight against the COVID-19 pandemic. Biosensors have previously shown the potential for cost-effective and accessible diagnostics, finding applications in settings where conventional, laboratorial techniques may not be readily employed. Paper- and cellulose-based biosensors can be particularly relevant in pandemic times, for the renewability, possibility of mass production with sustainable methodologies, and safe environmental disposal. In this review, paper-based devices and platforms targeting SARS-CoV-2 are showcased and discussed, as a means to achieve quick and low-cost PoC diagnosis, including detection methodologies for viral genomic material, viral antigen detection, and serological antibody testing. Devices targeting inflammatory markers relevant for COVID-19 are also discussed, as fast, reliable bedside diagnostic tools for patient treatment and follow-up.
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Affiliation(s)
- Tomás Pinheiro
- CENIMAT
i3N, Materials Science Department, Faculty of Science and Technology, Universidade NOVA de Lisboa and CEMOP/UNINOVA, Caparica 2829-516, Portugal
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
| | - A. Rita Cardoso
- CENIMAT
i3N, Materials Science Department, Faculty of Science and Technology, Universidade NOVA de Lisboa and CEMOP/UNINOVA, Caparica 2829-516, Portugal
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
- BioMark@ISEP,
School of Engineering, Polytechnic Institute
of Porto, R. Dr. António
Bernardino de Almeida, 431, Porto 4249-015, Portugal
- CEB,
Centre of Biological Engineering, University
of Minho, Braga 4710-057, Portugal
| | - Cristina E. A. Sousa
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
- BioMark@ISEP,
School of Engineering, Polytechnic Institute
of Porto, R. Dr. António
Bernardino de Almeida, 431, Porto 4249-015, Portugal
| | - Ana C. Marques
- CENIMAT
i3N, Materials Science Department, Faculty of Science and Technology, Universidade NOVA de Lisboa and CEMOP/UNINOVA, Caparica 2829-516, Portugal
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
| | - Ana P. M. Tavares
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
- BioMark@ISEP,
School of Engineering, Polytechnic Institute
of Porto, R. Dr. António
Bernardino de Almeida, 431, Porto 4249-015, Portugal
- CEB,
Centre of Biological Engineering, University
of Minho, Braga 4710-057, Portugal
| | - Ana Miguel Matos
- Faculty
of Pharmacy, University of Coimbra, Pólo das Ciências
da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Chemical
Engineering Processes and Forest Products Research Center, Coimbra 3000-548, Portugal
| | - Maria Teresa Cruz
- Faculty
of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Polo I, 1st Floor, Coimbra 3004-504, Portugal
| | - Felismina T. C. Moreira
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
- BioMark@ISEP,
School of Engineering, Polytechnic Institute
of Porto, R. Dr. António
Bernardino de Almeida, 431, Porto 4249-015, Portugal
| | - Rodrigo Martins
- CENIMAT
i3N, Materials Science Department, Faculty of Science and Technology, Universidade NOVA de Lisboa and CEMOP/UNINOVA, Caparica 2829-516, Portugal
| | - Elvira Fortunato
- CENIMAT
i3N, Materials Science Department, Faculty of Science and Technology, Universidade NOVA de Lisboa and CEMOP/UNINOVA, Caparica 2829-516, Portugal
| | - M. Goreti F. Sales
- BioMark@UC,
Faculty of Sciences and Technology, University
of Coimbra R. Sílvio Lima, Pólo II, 3030-790 Coimbra, Portugal
- BioMark@ISEP,
School of Engineering, Polytechnic Institute
of Porto, R. Dr. António
Bernardino de Almeida, 431, Porto 4249-015, Portugal
- CEB,
Centre of Biological Engineering, University
of Minho, Braga 4710-057, Portugal
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36
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Papadopoulos KI, Sutheesophon W, Manipalviratn S, Aw TC. Age and genotype dependent erythropoietin protection in COVID-19. World J Stem Cells 2021; 13:1513-1529. [PMID: 34786155 PMCID: PMC8567454 DOI: 10.4252/wjsc.v13.i10.1513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/23/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a "bait" for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.
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Affiliation(s)
| | | | - Somjate Manipalviratn
- Department of Reproductive Endocrinology, Jetanin Institute for Assisted Reproduction, Bangkok 10330, Thailand
| | - Tar-Choon Aw
- Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
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37
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Soni B, Singh S. COVID-19 co-infection mathematical model as guided through signaling structural framework. Comput Struct Biotechnol J 2021; 19:1672-1683. [PMID: 33815692 PMCID: PMC7997053 DOI: 10.1016/j.csbj.2021.03.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 12/23/2022] Open
Abstract
SARS-CoV-2 and Influenza co-infection turned out to be a huge threat in recent times. The clinical presentation and disease severity is common in both the infection condition. The present paper deals with studying co-infection model system through systems biology approaches. Understanding signaling regulation in COVID-19 and co-infection model systems aid in the development of network-based models thereby suggesting intervention points for therapeutics. This paper highlights the aim of revealing such perturbations to decipher opportune mediating cross talks characterizing the deadly viral disease. The comparative analysis of both the models reveals major signaling protein NFκB and STAT1 playing a crucial role in establishing co-infection. By targeting these proteins at cellular level, it might help modulating the release of potent pro-inflammatory cytokines thereby taming the severity of the disease symptoms. Mathematical models developed here are precisely tailored and serves as a first step towards co-infection model offering flexibility and pitching towards therapeutic investigation.
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Affiliation(s)
- Bhavnita Soni
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SPPU Campus, Pune 411007, India
| | - Shailza Singh
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SPPU Campus, Pune 411007, India
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38
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Luo H, Jia T, Chen J, Zeng S, Qiu Z, Wu S, Li X, Lei Y, Wang X, Wu W, Zhang R, Zou X, Feng T, Ding R, Zhang Y, Chen YQ, Sun C, Wang T, Fang S, Shu Y. The Characterization of Disease Severity Associated IgG Subclasses Response in COVID-19 Patients. Front Immunol 2021; 12:632814. [PMID: 33763078 PMCID: PMC7982848 DOI: 10.3389/fimmu.2021.632814] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/04/2021] [Indexed: 12/21/2022] Open
Abstract
Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1β was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.
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Affiliation(s)
- Huanle Luo
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
- Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Tingting Jia
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Jiamin Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Shike Zeng
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Zengzhao Qiu
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Shu Wu
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Xu Li
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuxuan Lei
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Xin Wang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Weihua Wu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Renli Zhang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Xuan Zou
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Tiejian Feng
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Ruxia Ding
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China
| | - Yue Zhang
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China
| | - Yao-Qing Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
- Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
- Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Tian Wang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yuelong Shu
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
- Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
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