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1.
Genet Med ; 24(8): 1653-1663, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1819495

ABSTRACT

PURPOSE: Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. METHODS: Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. RESULTS: We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. CONCLUSION: This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.


Subject(s)
COVID-19 , Aged , COVID-19/genetics , Collectins/genetics , Collectins/metabolism , Germ Cells , Humans , Lectins/genetics , SARS-CoV-2 , Whole Exome Sequencing
2.
Front Immunol ; 12: 650331, 2021.
Article in English | MEDLINE | ID: covidwho-1156125

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , COVID-19/immunology , Eosinophils/immunology , Lectins/immunology , Mast Cells/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Case-Control Studies , Cytokines/metabolism , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/virology , Host-Pathogen Interactions , Humans , Lectins/antagonists & inhibitors , Lectins/genetics , Lectins/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Mast Cells/virology , Mice, Transgenic , Peptide Hydrolases/metabolism , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Toll-Like Receptors/metabolism
3.
Viruses ; 13(1)2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1016260

ABSTRACT

Glycosylation, being the most abundant post-translational modification, plays a profound role affecting expression, localization and function of proteins and macromolecules in immune response to infection. Presented are the findings of a transcriptomic analysis performed using high-throughput functional genomics data from public repository to examine the altered transcription of the human glycosylation machinery in response to SARS-CoV-2 stimulus and infection. In addition to the conventional in silico functional enrichment analysis methods we also present results from the manual analysis of biomedical literature databases to bring about the biological significance of glycans and glycan-binding proteins in modulating the host immune response during SARS-CoV-2 infection. Our analysis revealed key immunomodulatory lectins, proteoglycans and glycan epitopes implicated in exerting both negative and positive downstream inflammatory signaling pathways, in addition to its vital role as adhesion receptors for SARS-CoV-2 pathogen. A hypothetical correlation of the differentially expressed human glycogenes with the altered host inflammatory response and the cytokine storm-generated in response to SARS-CoV-2 pathogen is proposed. These markers can provide novel insights into the diverse roles and functioning of glycosylation pathways modulated by SARS-CoV-2, provide avenues of stratification, treatment, and targeted approaches for COVID-19 immunity and other viral infectious agents.


Subject(s)
COVID-19/metabolism , Polysaccharides/metabolism , SARS-CoV-2/physiology , Biomarkers/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Databases, Genetic , Epitopes/genetics , Epitopes/metabolism , Gene Expression Profiling , Gene Expression Regulation , Gene Regulatory Networks , Glycosylation , Host-Pathogen Interactions , Humans , Inflammation , Lectins/genetics , Lectins/metabolism , Polysaccharides/genetics , Signal Transduction
4.
Proc Natl Acad Sci U S A ; 117(41): 25759-25770, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-807358

ABSTRACT

Human coronaviruses OC43 and HKU1 are respiratory pathogens of zoonotic origin that have gained worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spillover. All three viruses attach to 9-O-acetylated sialoglycans via spike protein S with hemagglutinin-esterase (HE) acting as a receptor-destroying enzyme. In BCoV, an HE lectin domain promotes esterase activity toward clustered substrates. OC43 and HKU1, however, lost HE lectin function as an adaptation to humans. Replaying OC43 evolution, we knocked out BCoV HE lectin function and performed forced evolution-population dynamics analysis. Loss of HE receptor binding selected for second-site mutations in S, decreasing S binding affinity by orders of magnitude. Irreversible HE mutations led to cooperativity in virus swarms with low-affinity S minority variants sustaining propagation of high-affinity majority phenotypes. Salvageable HE mutations induced successive second-site substitutions in both S and HE. Apparently, S and HE are functionally interdependent and coevolve to optimize the balance between attachment and release. This mechanism of glycan-based receptor usage, entailing a concerted, fine-tuned activity of two envelope protein species, is unique among CoVs, but reminiscent of that of influenza A viruses. Apparently, general principles fundamental to virion-sialoglycan interactions prompted convergent evolution of two important groups of human and animal pathogens.


Subject(s)
Coronavirus/physiology , Hemagglutinins, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Fusion Proteins/genetics , Virion/metabolism , Animals , Biological Evolution , Cell Line , Coronavirus/genetics , Coronavirus/metabolism , Coronavirus Infections/virology , Coronavirus OC43, Human/genetics , Coronavirus OC43, Human/metabolism , Coronavirus OC43, Human/physiology , Coronavirus, Bovine/genetics , Coronavirus, Bovine/metabolism , Coronavirus, Bovine/physiology , Hemagglutinins, Viral/chemistry , Hemagglutinins, Viral/metabolism , Humans , Lectins/genetics , Lectins/metabolism , Mice , Mutation , Protein Binding , Protein Domains , Receptors, Virus/metabolism , Selection, Genetic , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/metabolism , Virion/genetics , Virus Attachment , Virus Release
5.
Virus Res ; 289: 198163, 2020 11.
Article in English | MEDLINE | ID: covidwho-752747

ABSTRACT

BACKGROUND: Susceptibility to severe viral infections was reported to be associated with genetic variants in immune response genes using case reports and GWAS studies. SARS-CoV-2 is an emergent viral disease that caused millions of COVID-19 cases all over the world. Around 15 % of cases are severe and some of them are accompanied by dysregulated immune system and cytokine storm. There is increasing evidence that severe manifestations of COVID-19 might be attributed to human genetic variants in genes related to immune deficiency and or inflammasome activation (cytokine storm). OBJECTIVE: Identify the candidate genes that are likely to aid in explaining severe COVID-19 and provide insights to understand the pathogenesis of severe COVID-19. METHODS: In this article, we systematically reviewed genes related to viral susceptibility that were reported in human genetic studies (Case-reports and GWAS) to understand the role of host viral interactions and to provide insights into the pathogenesis of severe COVID-19. RESULTS: We found 40 genes associated with viral susceptibility and 21 of them were associated with severe SARS-CoV disease and severe COVID-19. Some of those genes were implicated in TLR pathways, others in C-lectin pathways, and others were related to inflammasome activation (cytokine storm). CONCLUSION: This compilation represents a list of candidate genes that are likely to aid in explaining severe COVID-19 which are worthy of inclusion in gene panels and during meta-analysis of different variants in host genetics studies of COVID-19. In addition, we provide several hypotheses for severe COVID-19 and possible therapeutic targets.


Subject(s)
Betacoronavirus , Coronavirus Infections/genetics , Pandemics , Pneumonia, Viral/genetics , Adolescent , Adult , Age Factors , Alleles , COVID-19 , Coronavirus Infections/drug therapy , Genetic Predisposition to Disease , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Humans , Inflammasomes/genetics , Lectins/genetics , Middle Aged , Models, Genetic , Molecular Targeted Therapy , Mutation , Polymorphism, Single Nucleotide , SARS-CoV-2 , Severe Acute Respiratory Syndrome/genetics , Signal Transduction/genetics , Toll-Like Receptor 3/genetics , Toll-Like Receptors/genetics , Virus Diseases/genetics , Young Adult
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