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1.
Physiol Res ; 69(3): 511-514, 2020 07 16.
Article in English | MEDLINE | ID: covidwho-655771

ABSTRACT

Knowledge of genomic interindividual variability could help us to explain why different manifestation of clinical severity of Covid-19 infection as well as modified pharmacogenetic relations can be expected during this pandemic condition.


Subject(s)
Coronavirus Infections/genetics , Pneumonia, Viral/genetics , Betacoronavirus/physiology , Genetic Predisposition to Disease , Host-Pathogen Interactions/genetics , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics
2.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Article in English | MEDLINE | ID: covidwho-654479

ABSTRACT

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Heat-Shock Proteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Host-Pathogen Interactions/drug effects , Pneumonia, Viral/drug therapy , Antiviral Agents/chemical synthesis , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Chromatin Assembly and Disassembly/drug effects , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation , Heat-Shock Proteins/agonists , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/agonists , Heterogeneous-Nuclear Ribonucleoproteins/antagonists & inhibitors , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Host-Pathogen Interactions/genetics , Humans , Molecular Targeted Therapy/methods , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Precursors/genetics , RNA Precursors/metabolism , Severity of Illness Index , Signal Transduction , Transcription, Genetic/drug effects , Virus Replication/drug effects
3.
Euro Surveill ; 25(28)2020 07.
Article in English | MEDLINE | ID: covidwho-647504

ABSTRACT

BackgroundA novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2.AimThe cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed.MethodsThe SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein.ResultsAn immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format.ConclusionThe cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.


Subject(s)
Antibodies, Monoclonal/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Sequence , Animals , Betacoronavirus/genetics , Blotting, Western , COS Cells , Chlorocebus aethiops , Conserved Sequence , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay/methods , Fluorescent Antibody Technique/methods , Genome, Viral , Mice , Pandemics , Peptidyl-Dipeptidase A/immunology , Plasmids , Pneumonia, Viral/genetics , Recombinant Proteins/immunology , SARS Virus/genetics , Sequence Alignment , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/genetics , Transfection , Vero Cells , Virus Integration
5.
Physiol Genomics ; 52(6): 255-268, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-632632

ABSTRACT

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Expression Profiling/methods , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Precision Medicine/methods , Humans , Pandemics , Transcription, Genetic , Viral Load
6.
In Vivo ; 34(5): 3027-3028, 2020.
Article in English | MEDLINE | ID: covidwho-740632

ABSTRACT

The FDA-approved drugs raloxifene and bazedoxifene could be among the best candidates to prevent mortality in severe COVID-19 patients. Raloxifene and bazedoxifene inhibit IL-6 signaling at therapeutic doses, suggesting they have the potential to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients, as is being shown with humanized antibodies blocking IL-6 signaling. In addition, raloxifene and bazedoxifene are selective estrogen receptor modulators with strong antiviral activity.


Subject(s)
Coronavirus Infections/drug therapy , Indoles/pharmacology , Pneumonia, Viral/drug therapy , Raloxifene Hydrochloride/pharmacology , Respiratory Distress Syndrome, Adult/drug therapy , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Receptors, Estrogen/antagonists & inhibitors , Respiratory Distress Syndrome, Adult/prevention & control , Respiratory Distress Syndrome, Adult/virology , Selective Estrogen Receptor Modulators/pharmacology , Signal Transduction/drug effects
8.
Genes (Basel) ; 11(9)2020 08 27.
Article in English | MEDLINE | ID: covidwho-738372

ABSTRACT

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.


Subject(s)
Basigin/genetics , Coronavirus Infections/genetics , Furin/genetics , Mutation , Pneumonia, Viral/genetics , Serine Endopeptidases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Exome , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Polymorphism, Single Nucleotide
9.
PLoS Pathog ; 16(8): e1008705, 2020 08.
Article in English | MEDLINE | ID: covidwho-732988

ABSTRACT

The recent outbreak of human infections caused by SARS-CoV-2, the third zoonotic coronavirus has raised great public health concern globally. Rapid and accurate diagnosis of this novel pathogen posts great challenges not only clinically but also technologically. Metagenomic next-generation sequencing (mNGS) and reverse-transcription PCR (RT-PCR) have been the most commonly used molecular methodologies. However, each has their own limitations. In this study, we developed an isothermal, CRISPR-based diagnostic for COVID-19 with near single-copy sensitivity. The diagnostic performances of all three technology platforms were also compared. Our study aimed to provide more insights into the molecular detection of SARS-CoV-2, and also to present a novel diagnostic option for this new emerging virus.


Subject(s)
Betacoronavirus/genetics , CRISPR-Cas Systems/genetics , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/genetics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/genetics , Bacteria/genetics , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Genes, Viral/genetics , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Molecular Diagnostic Techniques/economics , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/economics , Nucleic Acid Amplification Techniques/methods , Pandemics , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity
10.
J Transl Med ; 18(1): 321, 2020 08 24.
Article in English | MEDLINE | ID: covidwho-727282

ABSTRACT

BACKGROUND: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. METHODS: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program. RESULTS: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian. CONCLUSIONS: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.


Subject(s)
Betacoronavirus/physiology , Mutation, Missense , Peptidyl-Dipeptidase A/genetics , Protein Interaction Domains and Motifs/genetics , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Betacoronavirus/metabolism , Binding Sites/genetics , Coronavirus Infections/ethnology , Coronavirus Infections/genetics , Coronavirus Infections/virology , DNA Mutational Analysis/methods , Databases, Genetic , Genetic Predisposition to Disease/ethnology , Genetic Variation , Geography , Humans , Models, Molecular , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/ethnology , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Polymorphism, Single Nucleotide , Protein Binding , Protein Structure, Secondary/genetics , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization
11.
Gac Med Mex ; 156(4): 354-357, 2020.
Article in English | MEDLINE | ID: covidwho-722454

ABSTRACT

Introduction: Reports of dermatological manifestations in patients with COVID-19 suggest a possible cutaneous tropism of SARS-CoV-2; however, the capacity of this virus to infect the skin is unknown. Objective: To determine the susceptibility of the skin to SARS-CoV-2 infection based on the expression of viral entry factors ACE2 and TMPRSS2 in this organ. Method: A comprehensive analysis of human tissue gene expression databases was carried out looking for the presence of the ACE2 and TMPRSS2 genes in the skin. mRNA expression of these genes in skin-derived human cell lines was also assessed. Results: The analyses showed high co-expression of ACE2 and TMPRSS2 in the gastrointestinal tract and kidney, but not in the skin. Only the human immortalized keratinocyte HaCaT cell line expressed detectable levels of ACE2, and no cell line originating in the skin expressed TMPRSS2. Conclusions: Our results suggest that cutaneous manifestations in patients with COVID-19 cannot be directly attributed to the virus. It is possible that cutaneous blood vessels endothelial damage, as well as the effect of circulating inflammatory mediators produced in response to the virus, are the cause of skin involvement.


Subject(s)
Coronavirus Infections/complications , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/complications , Serine Endopeptidases/genetics , Skin Diseases, Viral/virology , Betacoronavirus/isolation & purification , Cell Line , Coronavirus Infections/genetics , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Pandemics , Pneumonia, Viral/genetics , Skin/virology , Skin Diseases, Viral/genetics , Viral Tropism/physiology , Virus Internalization
12.
Signal Transduct Target Ther ; 5(1): 156, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-717099

ABSTRACT

The global Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has affected more than eight million people. There is an urgent need to investigate how the adaptive immunity is established in COVID-19 patients. In this study, we profiled adaptive immune cells of PBMCs from recovered COVID-19 patients with varying disease severity using single-cell RNA and TCR/BCR V(D)J sequencing. The sequencing data revealed SARS-CoV-2-specific shuffling of adaptive immune repertories and COVID-19-induced remodeling of peripheral lymphocytes. Characterization of variations in the peripheral T and B cells from the COVID-19 patients revealed a positive correlation of humoral immune response and T-cell immune memory with disease severity. Sequencing and functional data revealed SARS-CoV-2-specific T-cell immune memory in the convalescent COVID-19 patients. Furthermore, we also identified novel antigens that are responsive in the convalescent patients. Altogether, our study reveals adaptive immune repertories underlying pathogenesis and recovery in severe versus mild COVID-19 patients, providing valuable information for potential vaccine and therapeutic development against SARS-CoV-2 infection.


Subject(s)
B-Lymphocytes/immunology , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Immunity, Cellular , Immunity, Humoral , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Antigens, Viral/genetics , Antigens, Viral/immunology , B-Lymphocytes/classification , B-Lymphocytes/virology , Betacoronavirus/immunology , Case-Control Studies , China , Convalescence , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Progression , Gene Expression , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/immunology , Humans , Immunologic Memory , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Receptors, Antigen, B-Cell/classification , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, T-Cell/classification , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index , Single-Cell Analysis , T-Lymphocytes/classification , T-Lymphocytes/virology
13.
Clin Immunol ; 219: 108572, 2020 10.
Article in English | MEDLINE | ID: covidwho-713545

ABSTRACT

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions/immunology , Pneumonia, Viral/genetics , Viral Proteins/genetics , Adult , Aged , Alleles , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Progression , Female , Gene Expression , Gene Frequency , Histocompatibility Antigens Class I/classification , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate , Male , Middle Aged , Pandemics , Peptides/genetics , Peptides/immunology , Pilot Projects , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Severity of Illness Index , Spain , Viral Proteins/immunology
14.
Am J Hum Genet ; 107(3): 381-402, 2020 09 03.
Article in English | MEDLINE | ID: covidwho-710246

ABSTRACT

The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, 36 of which involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (seven of which identified protective alleles) and 16 related to outcomes (three of which identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation in the study of COVID-19. We also discuss how previous studies may direct current lines of inquiry.


Subject(s)
Coronavirus Infections/genetics , Genetic Predisposition to Disease , Pneumonia, Viral/genetics , Animals , Betacoronavirus , Disease Reservoirs/veterinary , Humans , Pandemics , Receptors, Virus/genetics , Species Specificity
15.
Pan Afr Med J ; 36: 80, 2020.
Article in English | MEDLINE | ID: covidwho-709363

ABSTRACT

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has become a pandemic. There is currently no vaccine or effective treatment for COVID-19. Early diagnosis and management is key to favourable outcomes. In order to prevent more widespread transmission of the virus, rapid detection and isolation of confirmed cases is of utmost importance. Real time reverse transcriptase polymerase chain reaction (RT-PCR) is currently the "gold standard" for the detection of SARS-COV-2. There are several challenges associated with this test from sample collection to processing and the longer turnaround time for the results to be available. More rapid and faster diagnostic tests that may produce results within minutes to a few hours will be instrumental in controlling the disease. Serological tests that detect specific antibodies to the virus may be such options. In this review, we extensively searched for studies that compared RT-PCR with serological tests for the diagnosis of COVID-19. We extracted the data from the various selected studies that compared the different tests and summarised the available evidence to determine which test is more appropriate especially in Africa. We also reviewed the current evidence and the challenges for the genome sequencing of SARS-COV-2 in Africa. Finally, we discuss the relevance of the different diagnostic tests and the importance of genome sequencing in identifying potential therapeutic options for the control of COVID-19 in Africa.


Subject(s)
Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Genome, Human , Pneumonia, Viral/diagnosis , Africa/epidemiology , Betacoronavirus/isolation & purification , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Serologic Tests , Time Factors
17.
Int J Mol Sci ; 21(15)2020 Jul 23.
Article in English | MEDLINE | ID: covidwho-704878

ABSTRACT

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson's coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson's coefficients between -0.47 and -0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1-35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1-41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , HLA-B44 Antigen/genetics , HLA-C Antigens/genetics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Coronavirus Infections/immunology , Gene Frequency , Humans , Italy/epidemiology , Pandemics , Pneumonia, Viral/immunology , Prevalence , Registries , Regression Analysis
18.
Genes Immun ; 21(4): 269-272, 2020 08.
Article in English | MEDLINE | ID: covidwho-696402

ABSTRACT

The entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes. We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2500 individuals. Our data show significant variability in genetic determinants of ACE2 and TMPRSS2 expression among individuals and between populations, and indicate a genetic predisposition for lower expression levels of both key viral entry genes in African populations. These data suggest that host genetics related to viral entry mechanisms might influence interindividual variability in disease susceptibility and severity of COVID-19.


Subject(s)
Coronavirus Infections/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Serine Endopeptidases/genetics , Continental Population Groups/genetics , Coronavirus Infections/ethnology , Female , Humans , Male , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/ethnology , Serine Endopeptidases/metabolism
19.
Clin Sci (Lond) ; 134(15): 1991-2017, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-694110

ABSTRACT

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal "cytokine storm". Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.


Subject(s)
Betacoronavirus/physiology , Chiroptera/immunology , Coronavirus Infections/immunology , Heat-Shock Response , Pneumonia, Viral/immunology , Animals , Betacoronavirus/genetics , Chiroptera/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Coronavirus Infections/physiopathology , Heat-Shock Proteins/genetics , Heat-Shock Proteins/immunology , Humans , Interferons/immunology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Pneumonia, Viral/physiopathology
20.
Immunogenetics ; 72(6-7): 387-391, 2020 09.
Article in English | MEDLINE | ID: covidwho-690803

ABSTRACT

Covid-19 has caused worldwide devastation. IFIH1 is a pattern recognition receptor that senses coronavirus RNA and triggers interferon production as a first line of viral immune defense. The role of IFIH1 polymorphism, rs1990760 (C>T; aaA946T) in the epidemiology of viral infection is well studied, and the minor allele T resists viral infection. Knock-in mice with mutated IFIH1 protein (946T) for this allele have enhanced interferon production and protection from lethal viral infection. The minor allele frequency (Tmaf) varies widely from Africans (0.06 to 0.35) to Chinese (0.19 to 0.23) to Caucasians (0.56 to 0.69). During the initial days of infection when the social restrictions were not imposed, I show that the infection rate in Italy was lower as expected from its higher Tmaf (0.56) than that in China (Tmaf for southern China, 0.23). The infection rate in the USA and Spain was intermediate between those two countries despite higher Caucasian overall Tmaf (0.69), perhaps due to a more admixed African population in these countries. These analyses suggest that African-Americans and Chinese with low Tmaf of rs1990760 are more vulnerable to SARS-COV2 infection, apart from other genetic factors or socioeconomic conditions in these population. Taken together, an IFN-beta supplement might aid in preventing COVID-19 infection and help in development of herd immunity.


Subject(s)
African Americans/genetics , Coronavirus Infections/genetics , Genetic Predisposition to Disease , Interferon-Induced Helicase, IFIH1/genetics , Pneumonia, Viral/genetics , Asian Continental Ancestry Group , Betacoronavirus , China , Gene Frequency , Genotype , Humans , Interferon-beta , Italy , Pandemics , Polymorphism, Single Nucleotide , United States
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