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1.
Lancet Respir Med ; 9(5): 533-544, 2021 05.
Article in English | MEDLINE | ID: covidwho-1931217

ABSTRACT

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Cough/etiology , Inflammation/etiology , Nervous System Diseases/etiology , Neuroimmunomodulation , Cough/physiopathology , Humans , Inflammation/physiopathology , Nervous System Diseases/physiopathology , SARS-CoV-2 , Syndrome
2.
Lancet Respir Med ; 9(5): 533-544, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537202

ABSTRACT

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Cough/etiology , Inflammation/etiology , Nervous System Diseases/etiology , Neuroimmunomodulation , Cough/physiopathology , Humans , Inflammation/physiopathology , Nervous System Diseases/physiopathology , SARS-CoV-2 , Syndrome
3.
Arthritis Rheumatol ; 73(10): 1791-1799, 2021 10.
Article in English | MEDLINE | ID: covidwho-1391545

ABSTRACT

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Interleukin-18/blood , Interleukin-8/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Macrophage Activation Syndrome/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Diagnosis, Differential , Female , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/complications , Male , Middle Aged , Young Adult
5.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1365266

ABSTRACT

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Loss of Function Mutation , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Interferon Regulatory Factor-7/genetics , Male , Middle Aged , Severity of Illness Index , Toll-Like Receptor 3/genetics , Whole Exome Sequencing , Whole Genome Sequencing , Young Adult
6.
Immunology ; 164(3): 467-475, 2021 11.
Article in English | MEDLINE | ID: covidwho-1266332

ABSTRACT

A number of mechanisms have been proposed to explain the well-established link between diabetic status and an increased susceptibility to infection. Notably, diabetes has been shown to be one of the strongest factors influencing healthcare outcome in COVID-19 infections. Though it has long been noted that lymphocytes upregulate insulin receptors following immune activation, until recently, this observation has received little attention. Here, we point out key findings implicating dysregulated insulin signalling in immune cells as a possible contributing factor in the immune pathology associated with diabetes. Mechanistically, insulin, by activating the PI3K/Akt/mTOR pathway, regulates various aspects of both myeloid cells and lymphocytes, such as cell survival, metabolic reprogramming and the polarization and differentiation of immune cells. PI3K signalling is also supressed by immune checkpoint proteins, suggesting that insulin signalling may antagonize peripheral tolerance. Remarkably, it has also recently been shown that, following insulin binding, the insulin receptor translocates to the nucleus where it plays a key role in regulating the transcription of various immune-related genes, including pathways involved in viral infections. Taken together, these observations suggest that dysregulated insulin signalling may directly contribute to a defective immune response during COVID-19 infections.


Subject(s)
Blood Glucose/metabolism , COVID-19/metabolism , Diabetes Mellitus, Type 1/metabolism , Insulin/metabolism , Lymphocytes/metabolism , SARS-CoV-2/pathogenicity , Animals , Biomarkers/blood , COVID-19/immunology , COVID-19/physiopathology , COVID-19/virology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/physiopathology , Host-Pathogen Interactions , Humans , Immune Checkpoint Proteins/metabolism , Insulin Resistance , Lymphocytes/immunology , Lymphocytes/virology , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism
7.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1247462

ABSTRACT

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Loss of Function Mutation , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Interferon Regulatory Factor-7/genetics , Male , Middle Aged , Severity of Illness Index , Toll-Like Receptor 3/genetics , Whole Exome Sequencing , Whole Genome Sequencing , Young Adult
8.
Sci Rep ; 11(1): 9905, 2021 05 10.
Article in English | MEDLINE | ID: covidwho-1223111

ABSTRACT

The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, and mortality. Expression profiles represent snapshots of combined genetic, socio-environmental (including socioeconomic and environmental factors), and physiological effects on the molecular phenotype. As such, they have potential to improve biological understanding of differences among populations, and provide therapeutic biomarkers and environmental mitigation strategies. Here, we undertook a large-scale assessment of patterns of gene expression between African Americans and European Americans, mining RNA-Seq data from 25 non-diseased and diseased (tumor) tissue-types. We observed the widespread enrichment of pathways implicated in COVID-19 and integral to inflammation and reactive oxygen stress. Chemokine CCL3L3 expression is up-regulated in African Americans. GSTM1, encoding a glutathione S-transferase that metabolizes reactive oxygen species and xenobiotics, is upregulated. The little-studied F8A2 gene is up to 40-fold more highly expressed in African Americans; F8A2 encodes HAP40 protein, which mediates endosome movement, potentially altering the cellular response to SARS-CoV-2. African American expression signatures, superimposed on single cell-RNA reference data, reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. Our findings establish basal prognostic signatures that can be used to refine approaches to minimize risk of severe infection and improve precision treatment of COVID-19 for African Americans. To enable dissection of causes of divergent molecular phenotypes, we advocate routine inclusion of metadata on genomic and socio-environmental factors for human RNA-sequencing studies.


Subject(s)
African Americans/genetics , COVID-19/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Neoplasms/genetics , /genetics , COVID-19/epidemiology , COVID-19/virology , Chemokine CCL3/genetics , Gene Regulatory Networks , Glutathione Transferase/genetics , Humans , Neoplasms/classification , Neoplasms/ethnology , Nuclear Proteins/genetics , Pandemics , Prognosis , RNA-Seq/methods , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Socioeconomic Factors , United States/epidemiology
9.
Front Cardiovasc Med ; 8: 634291, 2021.
Article in English | MEDLINE | ID: covidwho-1221941

ABSTRACT

Anti-cancer treatment regimens can lead to both acute- and long-term myocardial injury due to off-target effects. Besides, cancer patients and survivors are severely immunocompromised due to the harsh effect of anti-cancer therapy targeting the bone marrow cells. Cancer patients and survivors can therefore be potentially extremely clinically vulnerable and at risk from infectious diseases. The recent global outbreak of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its infection called coronavirus disease 2019 (COVID-19) has rapidly become a worldwide health emergency, and on March 11, 2020, COVID-19 was declared a global pandemic by the World Health Organization (WHO). A high fatality rate has been reported in COVID-19 patients suffering from underlying cardiovascular diseases. This highlights the critical and crucial aspect of monitoring cancer patients and survivors for potential cardiovascular complications during this unprecedented health crisis involving the progressive worldwide spread of COVID-19. COVID-19 is primarily a respiratory disease; however, COVID-19 has shown cardiac injury symptoms similar to the cardiotoxicity associated with anti-cancer therapy, including arrhythmia, myocardial injury and infarction, and heart failure. Due to the significant prevalence of micro- and macro-emboli and damaged vessels, clinicians worldwide have begun to consider whether COVID-19 may in fact be as much a vascular disease as a respiratory disease. However, the underlying mechanisms and pathways facilitating the COVID-19-induced cardiac injury in cancer and non-cancer patients remain unclear. Investigations into whether COVID-19 cardiac injury and anti-cancer drug-induced cardiac injury in cancer patients and survivors might synergistically increase the cardiovascular complications and comorbidity risk through a "two-hit" model are needed. Identification of cardiac injury mechanisms and pathways associated with COVID-19 development overlapping with anti-cancer therapy could help clinicians to allow a more optimized prognosis and treatment of cancer survivors suffering from COVID-19. The following review will focus on summarizing the harmful cardiovascular risk of COVID-19 in cancer patients and survivors treated with an anti-cancer drug. This review will improve the knowledge of COVID-19 impact in the field of cardio-oncology and potentially improve the outcome of patients.

10.
Eur Rev Med Pharmacol Sci ; 25(7): 3122-3131, 2021 04.
Article in English | MEDLINE | ID: covidwho-1194853

ABSTRACT

OBJECTIVE: Transcriptome data related to severe acute respiratory syndrome-related coronavirus 2 (a novel coronavirus discovered in 2019, SARS-CoV-2) in GEO database were downloaded. Based on the data, influence of SARS-CoV-2 on human cells was analyzed and potential therapeutic compounds against the SARS-CoV-2 were screened. MATERIALS AND METHODS: R package "DESeq2" was used for differential gene analysis on the data of cells infected or non-infected with SARS-CoV-2. The "ClusterProfiler" package was used for GO functional annotation and KEGG pathway enrichment analysis of the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network of the DEGs was constructed through STRING website, and the key subset in the PPI network was identified after visualization by Cytoscape software. Connectivity Map (CMap) database was used to screen known compounds that caused genomic change reverse to that caused by SARS-CoV-2. RESULTS: By intersecting DEGs in two datasets, a total of 145 DEGs were screened out, among which 136 genes were upregulated and 9 genes were downregulated in SARS-CoV-2-infected cells. Functional enrichment analyses revealed that these genes were mainly associated with the pathways involved in viral infection, inflammatory response, and immunity. The CMap research found that there were three compounds with a median_tau_score less than -90, namely triptolide, tivozanib and daunorubicin. CONCLUSIONS: SARS-CoV-2 can cause abnormal changes in a large number of molecules and related signaling pathways in human cells, among which IL-17 and TNF signaling pathways may play a key role in pathogenic process of SARS-CoV-2. Here, three compounds that may be effective for the treatment of SARS-CoV-2 were screened, which would provide new options for improving treatment of patients infected with SARS-CoV-2.


Subject(s)
COVID-19/drug therapy , COVID-19/genetics , Drug Discovery , Gene Expression Profiling , Databases, Genetic , Databases, Pharmaceutical , Daunorubicin , Diterpenes , Down-Regulation , Epoxy Compounds , Gene Ontology , Gene Regulatory Networks , Humans , Molecular Targeted Therapy , Phenanthrenes , Phenylurea Compounds , Protein Interaction Maps , Quinolines , SARS-CoV-2 , Signal Transduction/genetics , Up-Regulation
11.
Hum Genomics ; 15(1): 18, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1136250

ABSTRACT

BACKGROUND: In the novel coronavirus pandemic, the high infection rate and high mortality have seriously affected people's health and social order. To better explore the infection mechanism and treatment, the three-dimensional structure of human bronchus has been employed in a better in-depth study on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We downloaded a separate microarray from the Integrated Gene Expression System (GEO) on a human bronchial organoids sample to identify differentially expressed genes (DEGS) and analyzed it with R software. After processing with R software, Gene Ontology (GO) and Kyoto PBMCs of Genes and Genomes (KEGG) were analyzed, while a protein-protein interaction (PPI) network was constructed to show the interactions and influence relationships between these differential genes. Finally, the selected highly connected genes, which are called hub genes, were verified in CytoHubba plug-in. RESULTS: In this study, a total of 966 differentially expressed genes, including 490 upregulated genes and 476 downregulated genes were used. Analysis of GO and KEGG revealed that these differentially expressed genes were significantly enriched in pathways related to immune response and cytokines. We construct protein-protein interaction network and identify 10 hub genes, including IL6, MMP9, IL1B, CXCL8, ICAM1, FGF2, EGF, CXCL10, CCL2, CCL5, CXCL1, and FN1. Finally, with the help of GSE150728, we verified that CXCl1, CXCL8, CXCL10, CCL5, EGF differently expressed before and after SARS-CoV-2 infection in clinical patients. CONCLUSIONS: In this study, we used mRNA expression data from GSE150819 to preliminarily confirm the feasibility of hBO as an in vitro model to further study the pathogenesis and potential treatment of COVID-19. Moreover, based on the mRNA differentiated expression of this model, we found that CXCL8, CXCL10, and EGF are hub genes in the process of SARS-COV-2 infection, and we emphasized their key roles in SARS-CoV-2 infection. And we also suggested that further study of these hub genes may be beneficial to treatment, prognostic prediction of COVID-19.


Subject(s)
Bronchi/virology , COVID-19/genetics , Gene Expression Regulation , Bronchi/physiology , Chemokine CXCL10/genetics , Epidermal Growth Factor/genetics , Host-Pathogen Interactions/genetics , Humans , Interleukin-8/genetics , Organoids , Protein Interaction Maps/genetics , Software
12.
Front Mol Biosci ; 7: 598583, 2020.
Article in English | MEDLINE | ID: covidwho-1082302

ABSTRACT

The constant rise of the death toll and cases of COVID-19 has made this pandemic a serious threat to human civilization. Understanding of host-SARS-CoV-2 interaction in viral pathogenesis is still in its infancy. In this study, we utilized a blend of computational and knowledgebase approaches to model the putative virus-host interplay in host signaling pathways by integrating the experimentally validated host interactome proteins and differentially expressed host genes in SARS-CoV-2 infection. While searching for the pathways in which viral proteins interact with host proteins, we discovered various antiviral immune response pathways such as hypoxia-inducible factor 1 (HIF-1) signaling, autophagy, retinoic acid-inducible gene I (RIG-I) signaling, Toll-like receptor signaling, fatty acid oxidation/degradation, and IL-17 signaling. All these pathways can be either hijacked or suppressed by the viral proteins, leading to improved viral survival and life cycle. Aberration in pathways such as HIF-1 signaling and relaxin signaling in the lungs suggests the pathogenic lung pathophysiology in COVID-19. From enrichment analysis, it was evident that the deregulated genes in SARS-CoV-2 infection might also be involved in heart development, kidney development, and AGE-RAGE signaling pathway in diabetic complications. Anomalies in these pathways might suggest the increased vulnerability of COVID-19 patients with comorbidities. Moreover, we noticed several presumed infection-induced differentially expressed transcription factors and epigenetic factors, such as miRNAs and several histone modifiers, which can modulate different immune signaling pathways, helping both host and virus. Our modeling suggests that SARS-CoV-2 integrates its proteins in different immune signaling pathways and other cellular signaling pathways for developing efficient immune evasion mechanisms while leading the host to a more complicated disease condition. Our findings would help in designing more targeted therapeutic interventions against SARS-CoV-2.

13.
Probiotics Antimicrob Proteins ; 13(4): 1138-1156, 2021 08.
Article in English | MEDLINE | ID: covidwho-1064620

ABSTRACT

With the alarming rise of infected cases and deaths, COVID-19 is a pandemic, affecting 220 countries worldwide. Until now, no specific treatment is available against SARS-CoV-2. The causal virus SARS-CoV-2 primarily infects lung cells, leading to respiratory illness ranging in severity from the common cold to deadly pneumonia. This, with comorbidities, worsens the clinical outcome, particularly for immunosuppressed individuals with COVID-19. Interestingly, the commensal gut microbiota has been shown to improve lung infections by modulating the immune system. Therefore, fine-tuning of the gut microbiome with probiotics could be an alternative strategy for boosting immunity and treating COVID-19. Here, we present a systematic biological network and meta-analysis to provide a rationale for the implementation of probiotics in preventing and/or treating COVID-19. We have identified 90 training genes from the literature analysis (according to PRISMA guidelines) and generated an association network concerning the candidate genes linked with COVID-19 and probiotic treatment. The functional modules and pathway enrichment analysis of the association network clearly show that the application of probiotics could have therapeutic effects on ACE2-mediated virus entry, activation of the systemic immune response, nlrp3-mediated immunomodulatory pathways, immune cell migration resulting in lung tissue damage and cardiovascular difficulties, and altered glucose/lipid metabolic pathways in the disease prognosis. We also demonstrate the potential mechanistic domains as molecular targets for probiotic applications to combat the viral infection. Our study, therefore, offers probiotics-mediated novel preventive and therapeutic strategies for COVID-19 warfare.


Subject(s)
COVID-19 , Probiotics , Antiviral Agents , Humans , Pandemics , SARS-CoV-2
14.
J Cereb Blood Flow Metab ; 41(6): 1179-1192, 2021 06.
Article in English | MEDLINE | ID: covidwho-1061015

ABSTRACT

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.


Subject(s)
COVID-19/pathology , Cerebrovascular Disorders/etiology , Stroke/etiology , Angiotensin-Converting Enzyme 2/metabolism , Blood-Brain Barrier/metabolism , COVID-19/complications , COVID-19/virology , Cerebrovascular Disorders/metabolism , Complement Activation , Humans , Renin-Angiotensin System , Spike Glycoprotein, Coronavirus/metabolism , Stroke/metabolism , Virus Internalization
15.
Sci Rep ; 11(1): 1930, 2021 01 21.
Article in English | MEDLINE | ID: covidwho-1041719

ABSTRACT

SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with respiratory complications and present signs of auto-inflammation. They also present with multiple comorbidities that are associated with poorer COVID-19 prognosis in the general population. All this might place DS individuals at higher risk of SARS-CoV-2 infection or poorer clinical outcomes. In order to get insight into the interplay between DS genes and SARS-cov2 infection and pathogenesis we identified the genes associated with the molecular pathways involved in COVID-19 and the host proteins interacting with viral proteins from SARS-CoV-2. We then analyzed the overlaps of these genes with HSA21 genes, HSA21 interactors and other genes consistently differentially expressed in DS (using public transcriptomic datasets) and created a DS-SARS-CoV-2 network. We detected COVID-19 protective and risk factors among HSA21 genes and interactors and/or DS deregulated genes that might affect the susceptibility of individuals with DS both at the infection stage and in the progression to acute respiratory distress syndrome. Our analysis suggests that at the infection stage DS individuals might be more susceptible to infection due to triplication of TMPRSS2, that primes the viral S protein for entry in the host cells. However, as the anti-viral interferon I signaling is also upregulated in DS, this might increase the initial anti-viral response, inhibiting viral genome release, viral replication and viral assembly. In the second pro-inflammatory immunopathogenic phase of the infection, the prognosis for DS patients might worsen due to upregulation of inflammatory genes that might favor the typical cytokine storm of COVID-19. We also detected strong downregulation of the NLRP3 gene, critical for maintenance of homeostasis against pathogenic infections, possibly leading to bacterial infection complications.


Subject(s)
COVID-19/genetics , Down Syndrome/genetics , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Cytokine Release Syndrome/immunology , Down Syndrome/epidemiology , Down Syndrome/immunology , Down Syndrome/virology , Gene Regulatory Networks , Host Microbial Interactions , Humans , Inflammation/immunology , Pandemics , Protective Factors , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Transcriptome/genetics
16.
Front Immunol ; 11: 590459, 2020.
Article in English | MEDLINE | ID: covidwho-1000088

ABSTRACT

BACKGROUND: SARS-CoV-2 causes ongoing pandemic coronavirus disease of 2019 (COVID-19), infects the cells of the lower respiratory tract that leads to a cytokine storm in a significant number of patients resulting in severe pneumonia, shortness of breathing, respiratory and organ failure. Extensive studies suggested the role of Vitamin D in suppressing cytokine storm in COVID-19 and reducing viral infection; however, the precise molecular mechanism is not clearly known. In this work, bioinformatics and systems biology approaches were used to understand SARS-CoV-2 induced cytokine pathways and the potential mechanism of Vitamin D in suppressing cytokine storm and enhancing antiviral response. RESULTS: This study used transcriptome data and identified 108 differentially expressed host genes (DEHGs) in SARS-CoV-2 infected normal human bronchial epithelial (NHBE) cells compared to control. Then, the DEHGs was integrated with the human protein-protein interaction data to generate a SARS-CoV-2 induced host gene regulatory network (SiHgrn). Analysis of SiHgrn identified a sub-network "Cluster 1" with the highest MCODE score, 31 up-regulated genes, and predominantly associated immune and inflammatory response. Interestingly, the iRegulone tool identified that "Cluster 1" is under the regulation of transcription factors STAT1, STAT2, STAT3, POU2F2, and NFkB1, collectively referred to as "host response signature network". Functional enrichment analysis with NDEx revealed that the "host response signature network" is predominantly associated with critical pathways, including "cytokines and inflammatory response", "non-genomic action of Vitamin D", "the human immune response to tuberculosis", and "lung fibrosis". Finally, in-depth analysis and literature mining revealed that Vitamin D binds with its receptor and could work through two different pathways: (i) it inhibits the expression of pro-inflammatory cytokines through blocking the TNF induced NFkB1 signaling pathway; and (ii) it initiates the expression of interferon-stimulating genes (ISGs) for antiviral defense program through activating the IFN-α induced Jak-STAT signaling pathway. CONCLUSION: This comprehensive study identified the pathways associated with cytokine storm in SARS-CoV-2 infection. The proposed underlying mechanism of Vitamin D could be promising in suppressing the cytokine storm and inducing a robust antiviral response in severe COVID-19 patients. The finding in this study urgently needs further experimental validations for the suitability of Vitamin D in combination with IFN-α to control severe COVID-19.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/prevention & control , SARS-CoV-2/drug effects , Systems Biology/methods , Vitamin D/therapeutic use , Antiviral Agents/therapeutic use , Cytokines/blood , Gene Expression Profiling , Humans , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/prevention & control , Transcriptome/genetics
17.
Eur J Pharmacol ; 887: 173594, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-996862

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR<0.05 and logFC ≥ 1). The DEGs were significantly involved in the immune and inflammatory response. The pathway analysis revealed the DEGs were found in influenza A, measles, cytokine signaling in the immune system, interleukin-4, interleukin -13, interleukin -17 signaling, and TNF signaling pathways. Protein-protein interaction analysis showed 10 hub genes (BIRC3, ICAM1, IRAK2, MAP3K8, S100A8, SOCS3, STAT5A, TNF, TNFAIP3, TNIP1). The regulatory network analysis showed significant transcription factors (TFs) that target DEGs, namely FOXC1, GATA2, YY1, FOXL1, NFKB1. Finally, drug repositioning analysis was performed with these 10 hub genes and showed that in silico validated three drugs with molecular docking. The transcriptomics signatures, molecular pathways, and regulatory biomolecules shed light on candidate biomarkers and drug targets which have potential roles to manage COVID-19. ICAM1 and TNFAIP3 were the key hubs that have demonstrated good binding affinities with repurposed drug candidates. Dabrafenib, radicicol, and AT-7519 were the top-scored repurposed drugs that showed efficient docking results when they tested with hub genes. The identified drugs should be further evaluated in molecular level wet-lab experiments in prior to clinical studies in the treatment of COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Drug Repositioning , Epithelial Cells/drug effects , Lung/cytology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Transcriptome , Antiviral Agents/therapeutic use , COVID-19 , Cells, Cultured , Computational Biology , Computer Simulation , Gene Expression Regulation/genetics , Humans , Pandemics , Signal Transduction/drug effects , Signal Transduction/genetics , Transcription Factors/genetics
18.
Respir Med ; 176: 106239, 2021 01.
Article in English | MEDLINE | ID: covidwho-933468

ABSTRACT

COVID-19 has quickly reached pandemic levels since it was first reported in December 2019. The virus responsible for the disease, named SARS-CoV-2, is enveloped positive-stranded RNA viruses. During its replication in the cytoplasm of host cells, the viral genome is transcribed into proteins, such as the structural protein spike domain S1, which is responsible for binding to the cell receptor of the host cells. Infected patients have initially flu-like symptoms, rapidly evolving to severe acute lung injury, known as acute respiratory distress syndrome (ARDS). ARDS is characterized by an acute and diffuse inflammatory damage into the alveolar-capillary barrier associated with a vascular permeability increase and reduced compliance, compromising gas exchange and causing hypoxemia. Histopathologically, this condition is known as diffuse alveolar damage which consists of permanent damage to the alveoli epithelial cells and capillary endothelial cells, with consequent hyaline membrane formation and eventually intracapillary thrombosis. All of these mechanisms associated with COVID-19 involve the phenotypic expression from different proteins transcription modulated by viral infection in specific pulmonary microenvironments. Therefore, this knowledge is fundamentally important for a better pathophysiological understanding and identification of the main molecular pathways associated with the disease evolution. Evidently, clinical findings, signs and symptoms of a patient are the phenotypic expression of these pathophysiological and molecular mechanisms of SARS-CoV-2 infection. Therefore, no findings alone, whether molecular, clinical, radiological or pathological axis are sufficient for an accurate diagnosis. However, their intersection and/or correlation are extremely critical for clinicians establish the diagnosis and new treatment perspectives.


Subject(s)
COVID-19/complications , COVID-19/pathology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Humans
19.
BMJ Open ; 10(8): e039849, 2020 08 11.
Article in English | MEDLINE | ID: covidwho-714383

ABSTRACT

INTRODUCTION: Data on race and ethnic disparities for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. We analysed sociodemographic factors associated with higher likelihood of SARS-CoV-2 infection and explore mediating pathways for race and ethnic disparities in the SARS-CoV-2 pandemic. METHODS: This is a cross-sectional analysis of the COVID-19 Surveillance and Outcomes Registry, which captures data for a large healthcare system, comprising one central tertiary care hospital, seven large community hospitals and an expansive ambulatory/emergency care network in the Greater Houston area. Nasopharyngeal samples for individuals inclusive of all ages, races, ethnicities and sex were tested for SARS-CoV-2. We analysed sociodemographic (age, sex, race, ethnicity, household income, residence population density) and comorbidity (Charlson Comorbidity Index, hypertension, diabetes, obesity) factors. Multivariable logistic regression models were fitted to provide adjusted OR (aOR) and 95% CI for likelihood of a positive SARS-CoV-2 test. Structural equation modelling (SEM) framework was used to explore three mediation pathways (low income, high population density, high comorbidity burden) for the association between non-Hispanic black (NHB) race, Hispanic ethnicity and SARS-CoV-2 infection. RESULTS: Among 20 228 tested individuals, 1551 (7.7%) tested positive. The overall mean (SD) age was 51.1 (19.0) years, 62% were females, 22% were black and 18% were Hispanic. NHB and Hispanic ethnicity were associated with lower socioeconomic status and higher population density residence. In the fully adjusted model, NHB (vs non-Hispanic white; aOR, 2.23, CI 1.90 to 2.60) and Hispanic ethnicity (vs non-Hispanic; aOR, 1.95, CI 1.72 to 2.20) had a higher likelihood of infection. Older individuals and males were also at higher risk of infection. The SEM framework demonstrated a significant indirect effect of NHB and Hispanic ethnicity on SARS-CoV-2 infection mediated via a pathway including residence in densely populated zip code. CONCLUSIONS: There is strong evidence of race and ethnic disparities in the SARS-CoV-2 pandemic that are potentially mediated through unique social determinants of health.


Subject(s)
Coronavirus Infections/ethnology , Health Status Disparities , Pandemics , Pneumonia, Viral/ethnology , Race Factors , Adult , African Americans/statistics & numerical data , Aged , Betacoronavirus , COVID-19 , Comorbidity , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Middle Aged , Population Density , Population Surveillance , Registries , SARS-CoV-2 , Socioeconomic Factors , Texas/epidemiology , /statistics & numerical data
20.
Eur Rev Med Pharmacol Sci ; 24(13): 7497-7505, 2020 07.
Article in English | MEDLINE | ID: covidwho-676904

ABSTRACT

OBJECTIVE: The specific mechanism of cytokine storm in COVID-19 infected patients is not clear. This study aims to identify the key genes that cause cytokine storm in COVID-19 infected patients. MATERIALS AND METHODS: We conducted a difference analysis on the GSE147507 data set. The analysis results are combined with immune genes to obtain immune-related genes among the differential genes. Finally, GO enrichment analysis, PPI analysis, core gene identification, and ssGSEA enrichment analysis were performed on the new gene set. RESULTS: A total of 232 differential genes were screened out. After merging with immune genes, a total of 29 immune-related genes were obtained. Further analysis revealed that the genes were enriched in 16 pathways, and the protein interaction network had a total of 29 nodes and 139 edges. After screening, the core gene was CXCL10. The ssGSEA results of CXCL10 showed that CD4 and CD8 immune-related signature were significantly enriched in high CXCL10 expression, and the samples with low CXCL10 expression were significantly enriched with monocytes and DC immune-related signature. CONCLUSIONS: CXCL10 may be a key gene related to the cytokine storm of COVID-19 infection, and it is expected to become the therapeutic target.


Subject(s)
Chemokine CXCL10/genetics , Coronavirus Infections/genetics , Pneumonia, Viral/genetics , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CXCL10/immunology , Coronavirus Infections/immunology , Humans , Pandemics , Pneumonia, Viral/immunology , Protein Interaction Maps/genetics , Protein Interaction Maps/immunology , SARS-CoV-2
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