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1.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
2.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574052

ABSTRACT

Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/administration & dosage , Interleukin-17/administration & dosage , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
3.
Med Sci Monit ; 27: e935005, 2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1464039

ABSTRACT

Recent studies on the pathogenesis and clinical spectrum of human disease following infection with the new human pathogen, SARS-CoV-2, have identified the varied presentations and sequelae of COVID-19. Acute 'cytokine storm' in severe COVID-19 results in multiorgan damage due to vascular hyperpermeability, edema, and hypercoagulation. The long-term consequences of infection from SARS-CoV-2 include long COVID. or post-COVID syndrome, and multisystem inflammatory syndrome in children (MIS-C). Several case reports of multisystem inflammatory syndrome in adults (MIS-A) have shown the presentation at more than four weeks after initial infection with SARS-CoV-2 in adults more than 21 years of age. In September 2021, a published systematic review of the literature identified 221 patients with MIS-A, representing the most comprehensive clinical study to date. MIS-A occurs in the post-acute COVID-19 period. The pathogenesis may involve a dysregulated antibody-mediated immune response, similar to MIS-C. Therefore, patients with MIS-A may respond to supportive therapies that control hyperinflammation. This Editorial aims to describe MIS-A and discuss COVID-19 as a spectrum of hyperinflammatory disease in terms of severity, extent, duration, and patient age.


Subject(s)
COVID-19/complications , Systemic Inflammatory Response Syndrome/etiology , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/immunology
4.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1437669

ABSTRACT

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Basigin/antagonists & inhibitors , Basigin/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , COVID-19/genetics , Chlorocebus aethiops , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells
5.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1384240

ABSTRACT

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS-CoV-2 is an emerging viral disease that triggers hyper-inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS-CoV-2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS-CoV-2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper-inflammatory state in SARS-CoV-2 patients.


Subject(s)
COVID-19/immunology , Coronavirus Papain-Like Proteases/chemistry , Cytokine Release Syndrome/immunology , Neoplasm Proteins/chemistry , Poly(ADP-ribose) Polymerases/chemistry , SARS-CoV-2/immunology , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Computer Simulation , Consensus Sequence , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Macrophages/immunology , Macrophages/virology , Molecular Docking Simulation , Molecular Mimicry , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sequence Alignment , Sequence Homology, Amino Acid , Thermodynamics
6.
FASEB J ; 35(9): e21798, 2021 09.
Article in English | MEDLINE | ID: covidwho-1334263

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Subject(s)
COVID-19/complications , Calgranulin A/physiology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Pandemics , Respiratory Distress Syndrome/etiology , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/pharmacology , COVID-19/genetics , COVID-19/pathology , Calgranulin A/blood , Calgranulin A/genetics , Chemokine CXCL11/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Disaccharides/pharmacology , Disaccharides/therapeutic use , Disease Models, Animal , Drug Discovery , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Inflammation/genetics , Inflammation/pathology , Lung/metabolism , Lung/pathology , Lung/virology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymphocyte Antigen 96/physiology , Macaca mulatta , Mice , Mice, Transgenic , Models, Biological , Mutation , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , Species Specificity , Sugar Phosphates/pharmacology , Sugar Phosphates/therapeutic use , Toll-Like Receptor 4/physiology , Up-Regulation , Virus Internalization
7.
Exp Mol Med ; 53(7): 1116-1123, 2021 07.
Article in English | MEDLINE | ID: covidwho-1307318

ABSTRACT

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/prevention & control , Interleukin-6/genetics , Receptors, Interleukin-6/genetics , Antibodies, Monoclonal, Humanized/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Cytokines/genetics , Cytokines/metabolism , Endothelium, Vascular/immunology , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Sepsis/genetics , Sepsis/immunology , Sepsis/pathology , Sepsis/prevention & control
8.
Viruses ; 13(6)2021 06 03.
Article in English | MEDLINE | ID: covidwho-1259622

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a 'cytokine storm.' In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.


Subject(s)
COVID-19/immunology , Chemokine CXCL10/genetics , Chemokine CXCL11/genetics , Chemokine CXCL9/genetics , Proto-Oncogene Proteins c-akt/metabolism , Up-Regulation , Angiotensin-Converting Enzyme 2/genetics , Animals , Cell Line , Chemokine CXCL10/immunology , Chemokine CXCL11/immunology , Chemokine CXCL9/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Humans , Inflammation , Lung/cytology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Signal Transduction/immunology
9.
Stem Cells Dev ; 30(15): 758-772, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1254367

ABSTRACT

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.


Subject(s)
Cytokine Release Syndrome/prevention & control , Extracellular Vesicles/physiology , Mesenchymal Stem Cells/cytology , SARS-CoV-2/physiology , Wharton Jelly/cytology , Adult , Aged , COVID-19/blood , COVID-19/complications , COVID-19/metabolism , COVID-19/therapy , Cells, Cultured , Coculture Techniques , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/metabolism , Diabetes Complications/blood , Diabetes Complications/metabolism , Diabetes Complications/therapy , Diabetes Complications/virology , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Diabetes Mellitus/therapy , Diabetes Mellitus/virology , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Glucose/metabolism , Glucose/pharmacology , Humans , Inflammation Mediators/metabolism , Male , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/physiology , Pregnancy , Toxins, Biological/metabolism , Toxins, Biological/pharmacology , Umbilical Cord/cytology , Uremia/blood , Uremia/complications , Uremia/metabolism , Uremia/therapy
10.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1206838

ABSTRACT

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS-CoV-2 is an emerging viral disease that triggers hyper-inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS-CoV-2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS-CoV-2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper-inflammatory state in SARS-CoV-2 patients.


Subject(s)
COVID-19/immunology , Coronavirus Papain-Like Proteases/chemistry , Cytokine Release Syndrome/immunology , Neoplasm Proteins/chemistry , Poly(ADP-ribose) Polymerases/chemistry , SARS-CoV-2/immunology , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Computer Simulation , Consensus Sequence , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Macrophages/immunology , Macrophages/virology , Molecular Docking Simulation , Molecular Mimicry , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sequence Alignment , Sequence Homology, Amino Acid , Thermodynamics
11.
Eur J Hum Genet ; 29(8): 1312-1315, 2021 08.
Article in English | MEDLINE | ID: covidwho-1191639

ABSTRACT

Critically ill coronavirus disease 2019 (COVID-19) is characterized by severe cytokine storms, a hyperinflammatory condition intimately related to the development of fatal outcomes. Why some individuals seem particularly vulnerable to severe cytokine storms is still unknown. Primary immunodeficiency (PID)-related genes are inherited factors that dysregulate host inflammatory responses to infection, especially hemophagocytic lymphohistiocytosis (HLH)-related genes, established as contributors to the development of excessive cytokine storms. We analyzed the association between PID gene variants with severe cytokine storms in COVID-19. We conducted whole-exome sequencing in 233 hospitalized COVID-19 patients and identified four PID gene (UNC13D, AP3B1, RNF168, DHX58) variants were significantly enriched in COVID-19 patients experiencing severe cytokine storms. The total percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical HLH genes, was dramatically higher in high-level cytokine group than in low-level group (33.3 vs. 5.7%, P < 0.001). Germline variants in UNC13D and AP3B1 were associated with the development of severe cytokine storms, fatal outcomes in COVID-19. These findings advance the understanding of individual susceptibility to severe cytokine storms and help optimize the current management of COVID-19.


Subject(s)
Adaptor Protein Complex 3/genetics , Adaptor Protein Complex beta Subunits/genetics , COVID-19/genetics , COVID-19/pathology , Membrane Proteins/genetics , Adaptor Protein Complex 3/metabolism , Adaptor Protein Complex beta Subunits/metabolism , Aged , COVID-19/immunology , COVID-19/metabolism , Cytokine Release Syndrome/genetics , Humans , Lymphohistiocytosis, Hemophagocytic/genetics , Membrane Proteins/metabolism , Middle Aged
12.
Expert Rev Proteomics ; 18(2): 83-91, 2021 02.
Article in English | MEDLINE | ID: covidwho-1182939

ABSTRACT

Introduction: The cytokine storm is a form of excessive systemic inflammatory reaction triggered by a myriad of factors that may lead to multi-organ failure, and finally to death. The cytokine storm can occur in a number of infectious and noninfectious diseases including COVID-19, sepsis, ebola, avian influenza, and graft versus host disease, or during the severe inflammatory response syndrome.Area covered: This review mainly focuses on the most common and well-known methods of protein studies (PAGE, SDS-PAGE, and high- performance liquid chromatography). It also discusses other modern technologies in proteomics like mass spectrometry, soft ionization techniques, cytometric bead assays, and the next generation of microarrays that have been used to get an in-depth understanding of the pathomechanisms involved during the cytokine storm.Expert opinion: Overactivation of leukocytes drives the production and secretion of inflammatory cytokines fueling the cytokine storm. These events lead to a systemic hyper-inflammation, circulatory collapse and shock, and finally to multiorgan failure. Therefore, monitoring the patient's systemic cytokine levels with proteomic technologies that are redundant, economical, and require minimal sample volume for real-time assessment might help in a better clinical evaluation and management of critically ill patients.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokines/genetics , Proteomics/methods , COVID-19/genetics , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokines/biosynthesis , Humans , Immunoassay/methods , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
13.
Mediators Inflamm ; 2021: 6635925, 2021.
Article in English | MEDLINE | ID: covidwho-1175215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/genetics , RNA/blood , RNA/genetics , SARS-CoV-2 , Adult , Aged , COVID-19/complications , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/genetics , Cytokines/biosynthesis , Cytokines/genetics , Female , Gene Expression , Humans , Inflammation Mediators/blood , Male , MicroRNAs/blood , MicroRNAs/genetics , Middle Aged , Pandemics , Protein Interaction Maps/genetics , RNA, Long Noncoding/blood , RNA, Long Noncoding/genetics , RNA, Messenger/blood , RNA, Messenger/genetics , Sequence Analysis, RNA , Signal Transduction , Whole Exome Sequencing , Young Adult
14.
Iran J Immunol ; 18(1): 65-73, 2021 03.
Article in English | MEDLINE | ID: covidwho-1159031

ABSTRACT

BACKGROUND: The role of cytokine storm in the immunopathogenesis of coronavirus disease 2019 (COVID-19) has been implicated. OBJECTIVE: To determine the association of microRNA (miRNA)-10b and serum levels of IL-2 and IL-8 in patients with COVID-19. METHODS: Blood samples were obtained from 33 COVID-19 patients and 29 healthy subjects. After RNA extraction and cDNA synthesis, the transcript level of miR-10b was determined by Real-time PCR. In addition, the serum levels of IL-2 and IL-8 were measured in subjects using ELISA. RESULTS: The patient group comprised of 33 patients with COVID-19 (62.4 ± 3.7 years old), 13 (39%) males and 20 (61%) females. In the control group, 29 subjects (56.6 ± 1.6 years old), 9 (31%) males and 20 (69%) females, were included. The expression of miR-10b was significantly downregulated in the peripheral blood of COVID-19 patients in comparison to the healthy controls (fold change= 0.12, P< 0.0001). The levels of IL-2 (P< 0.001) and IL-8 (P< 0.001) were significantly increased in the serum samples of COVID-19 patients compared to the healthy subjects. The expression level of miR-10b was correlated significantly with the serum levels of IL-2 and IL-8 as well as with the age of patients, ESR and CRP levels. CONCLUSIONS: miR-10b is downregulated in the COVID-19 patients and might result in increased levels of IL-2 and IL-8, hence contributing to cytokine storm.


Subject(s)
COVID-19/blood , Circulating MicroRNA/blood , Interleukin-2/blood , Interleukin-8/blood , MicroRNAs/blood , SARS-CoV-2/pathogenicity , Aged , Biomarkers/blood , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Circulating MicroRNA/genetics , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Female , Host-Pathogen Interactions , Humans , Male , MicroRNAs/genetics , Middle Aged , SARS-CoV-2/immunology
15.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1145418

ABSTRACT

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Dental Plaque/immunology , Host-Pathogen Interactions/immunology , Periodontitis/immunology , SARS-CoV-2/pathogenicity , Stress, Psychological/immunology , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Dental Plaque/complications , Dental Plaque/genetics , Dental Plaque/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lung/immunology , Lung/pathology , Lung/virology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , Periodontitis/complications , Periodontitis/genetics , Periodontitis/virology , SARS-CoV-2/immunology , Signal Transduction , Stress, Psychological/complications , Stress, Psychological/genetics , Stress, Psychological/virology , Tooth/immunology , Tooth/pathology , Tooth/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
16.
Front Immunol ; 11: 592622, 2020.
Article in English | MEDLINE | ID: covidwho-1081192

ABSTRACT

SARS-CoV-2 causes the ongoing COVID-19 pandemic. Natural SARS-COV-2 infection has been detected in dogs, cats and tigers. However, the symptoms in canines and felines were mild. The underlying mechanisms are unknown. Excessive activation of inflammasome pathways can trigger cytokine storm and severe damage to host. In current study, we performed a comparative genomics study of key components of inflammasome and pyroptosis pathways in dogs, cats and tigers. Cats and tigers do not have AIM2 and NLRP1. Dogs do not contain AIM2, and encode a short form of NLRC4. The activation sites in GSDMB were absent in dogs, cats and tigers, while GSDME activation sites in cats and tigers were abolished. We propose that deficiencies of inflammasome and pyroptosis pathways might provide an evolutionary advantage against SARS-CoV-2 by reducing cytokine storm-induced host damage. Our findings will shed important lights on the mild symptoms in canines and felines infected with SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/veterinary , Cat Diseases , Dog Diseases , Inflammasomes/immunology , Pyroptosis/immunology , Animals , Cat Diseases/immunology , Cat Diseases/virology , Cats , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Dog Diseases/immunology , Dog Diseases/virology , Dogs , Genomics , Humans , Inflammasomes/genetics , Pyroptosis/genetics , SARS-CoV-2 , Tigers
17.
Emerg Microbes Infect ; 10(1): 266-276, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1057796

ABSTRACT

SARS-CoV-2 has claimed 2,137,908 lives in more than a year. Some COVID-19 patients experience sudden and rapid deterioration with the onset of fatal cytokine storm syndrome (CSS), which have increased interest in CSS's mechanisms, diagnosis and therapy. Although the prototypic concept of CSS was first proposed 116 years ago, we have only begun to study and understand CSS for less than 30 years. Actually, diseases under CSS umbrella include familial/primary and secondary hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), infection-associated hemophagocytic syndrome, cytokine release syndrome (CRS), and cytokine storm (CS). Hematologic malignancies and autoimmune diseases that cause CSS are named malignancy-associated hemophagocytic syndrome (MAHS) and MAS, respectively. In-depth research on the pathogenesis of HLH/CSS has greatly increased the number of patients that were able to be definitively diagnosed with HLH/CSS. However, it should be emphasized that HLH/CSS diagnosis is difficult at the early stages due to the non-specific clinical signs and symptoms, which tends to result in missed and incorrect diagnoses. Therefore, clinicians should not only possess extensive clinical experience to ensure high sensitivity to the characteristics of HLH/CSS but must also be familiar with HLH-2004/2009 diagnostic criteria, and HScore methods. The paper concisely comment evolution of CSS classifications, cytokines associated with CSS, evolution of CSS diagnostic criteria and importance of the correct identification of hemophagocytes in diagnosing CSS, which is timely and may benefit clinicians familiar HLH-2004/2009 diagnostic criteria, and HScore methods. In addition, clinicians must also understand that there are some limitations to these diagnostic criteria. Abbreviations: aBMT: autologous bone marrow transplantation; CAR-T: chimeric antigen receptor-engineered T-cell; COVID-19: coronavirus disease 2019; CSS: cytokine storm syndrome; HLH: hemophagocytic lymphohistiocytosis; MAS: macrophage activation syndrome; CRS: cytokine release syndrome; CS: cytokine storm; MAHS: malignancy-associated hemophagocytic syndrome; IAHS: infection-associated hemophagocytic syndrome; fHLH/pHLH: familial/primary hemophagocytic lymphohistiocytosis; sHLH: secondary hemophagocytic lymphohistiocytosis; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TCR-T, T-cell receptor-engineered T-cell.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Animals , COVID-19/diagnosis , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
18.
Med Hypotheses ; 146: 110415, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1014715

ABSTRACT

COVID-19 is characterized by two major clinical phases, the SARS-CoV-2 infection of target cells and tissues, and a deep inflammatory state, known as "cytokine storm", caused by activation of pro-inflammatory genes, such as NF-kB, STAT-3, IL-6, IL-8, IL-1ß. Among possible anti-inflammatory agents, the "microRNA targeting" should be carefully considered, since it is well known that microRNAs are deeply involved in the expression of cytokines, chemokines and growth factors. The working general hypothesis is that targeting the microRNA network might be important for the development of therapeutic approaches to counteract the COVID-19 induction of inflammatory response. This hypothesis is based on several publications demonstrating the use of miRNA mimics for inhibitory effects on the production of proteins characterizing the COVID-19 "cytokine storm".


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , MicroRNAs/genetics , Models, Biological , 3' Untranslated Regions/genetics , Anti-Inflammatory Agents/pharmacology , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/therapy , MicroRNAs/therapeutic use , Molecular Mimicry , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , SARS-CoV-2
19.
Probl Endokrinol (Mosk) ; 66(4): 9-15, 2020 09 01.
Article in Russian | MEDLINE | ID: covidwho-994559

ABSTRACT

Genes of HLA system (Human Leukocyte Antigen) play an essential role in the normal functioning of the immune system. There are three classes of genes: I, II, and III. The function of HLA molecules class I is to present antigens of peptides from the cytoplasm to T-lymphocytes on the cell surface, and class II - to present antigens of peptides from the extracellular space. In the classical view, the pathological activation of the immune system in patients with a genetic predisposition can result in the development of autoimmune diseases. However, the influence of this system on the development of non-autoimmune diseases, their severity and prognosis, has been recently considered. Besides, HLA molecules provide a presentation of various infectious agents. In this connection, the loci of the main histocompatibility complex can be considered candidates for determining the genetic predisposition to infectious diseases themselves and their course. This review hypothesizes that specific variants of HLA genes may cause the formation of a «cytokine storm¼ in patients with COVID-19. Identification of a group of patients with particular genetic variations that cause violation of immune tolerance and hyperresponse in the setting of viral infection will help to optimize the algorithm for disease prevention and treatment of such patients and, as a result, to reduce the severity of the epidemiological situation.


Subject(s)
Autoimmune Diseases/immunology , COVID-19/genetics , Cytokine Release Syndrome/genetics , HLA Antigens/immunology , Alleles , Autoimmune Diseases/epidemiology , Autoimmune Diseases/genetics , Autoimmune Diseases/virology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Genetic Predisposition to Disease , HLA Antigens/genetics , Humans , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
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