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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
3.
Gac Med Mex ; 156(4): 328-333, 2020.
Article in English | MEDLINE | ID: covidwho-732611

ABSTRACT

In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/virology , Pneumonia, Viral/virology , Testis/virology , Basigin/genetics , Coronavirus Infections/physiopathology , Gene Expression Regulation , Humans , Male , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/physiopathology , Serine Endopeptidases/genetics , Virus Latency
4.
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
5.
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
7.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-709757

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Disease Models, Animal , Interferon Type I/metabolism , Mice/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Animals , Cell Line, Tumor , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dependovirus/genetics , Female , Humans , Inflammation/metabolism , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , Pandemics , Parvoviridae Infections/metabolism , Parvoviridae Infections/virology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Signal Transduction/genetics , Virus Replication/genetics
8.
EBioMedicine ; 58: 102907, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-704827

ABSTRACT

BACKGROUND: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful. METHODS: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed. FINDINGS AND INTERPRETATION: SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Kallikrein-Kinin System/drug effects , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Renin-Angiotensin System/drug effects
9.
J Infect Dis ; 222(4): 551-555, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-704462

ABSTRACT

We simulated 3 transmission modes, including close-contact, respiratory droplets and aerosol routes, in the laboratory. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be highly transmitted among naive human angiotensin-converting enzyme 2 (hACE2) mice via close contact because 7 of 13 naive hACE2 mice were SARS-CoV-2 antibody seropositive 14 days after being introduced into the same cage with 3 infected-hACE2 mice. For respiratory droplets, SARS-CoV-2 antibodies from 3 of 10 naive hACE2 mice showed seropositivity 14 days after introduction into the same cage with 3 infected-hACE2 mice, separated by grids. In addition, hACE2 mice cannot be experimentally infected via aerosol inoculation until continued up to 25 minutes with high viral concentrations.


Subject(s)
Betacoronavirus , Coronavirus Infections/transmission , Pneumonia, Viral/transmission , Aerosols , Anal Canal/virology , Animals , Antibodies, Viral/blood , Betacoronavirus/genetics , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Chlorocebus aethiops , Female , Humans , Immunoglobulin G/blood , Lung/pathology , Lung/virology , Male , Mice , Mice, Transgenic , Pandemics , Peptidyl-Dipeptidase A/genetics , Pharynx/virology , RNA, Viral/isolation & purification , Respiratory System/virology , Risk , Specific Pathogen-Free Organisms , Time Factors , Vero Cells , Viral Load , Weight Loss
10.
Parasit Vectors ; 13(1): 409, 2020 Aug 10.
Article in English | MEDLINE | ID: covidwho-707467

ABSTRACT

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide. Recent evidence raised the question about the possibility that cats may be a domestic host for SARS-CoV-2 with unknown implications in disease dissemination. Based on the fact that the domestic cat flea, Ctenocephalides felis, are abundant ectoparasites infesting humans, companion animals and wildlife and that coronavirus-like agents have been identified in the ectoparasite tick vector, Ixodes uriae of seabirds, herein we considered the presence of coronaviruses in general and SARS-CoV-2 in particular in C. felis. We identified coronavirus-derived and cell receptor angiotensin-converting enzyme RNA/proteins in C. felis. Although current evidence suggests that pets are probably dead-end-hosts with small risk of transmission to humans, our results suggested that cat flea may act as biological and/or mechanical vectors of SARS-CoV. Although preliminary, these results indicate a possibility of ectoparasites acting as reservoirs and vectors of SARS-CoV and related beta-coronavirus although with little disease risk due to systemic transmission route, low viremia, virus attenuation or other unknown factors. These results support the need to further study the role of animal SARS-CoV-2 hosts and their ectoparasite vectors in COVID-19 disease spread.


Subject(s)
Coronavirus Infections/veterinary , Coronavirus/isolation & purification , Ctenocephalides/virology , Insect Vectors/virology , Pneumonia, Viral/veterinary , Amino Acid Sequence , Animals , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Coronavirus Infections/transmission , Coronavirus Infections/virology , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology
11.
Int J Antimicrob Agents ; 56(3): 106078, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-701532

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria. Moreover, their antiviral properties have been previously studied, including against coronaviruses, where evidence of efficacy has been found. In the current race against time triggered by the COVID-19 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ. These could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low-molecular-weight heparin, aimed at preventing acute respiratory distress syndrome (ARDS)-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. This review also re-examines the real information provided by some of the published alarming reports, although concluding that cardiac toxicity should in any case be stringently monitored in patients receiving CQ/HCQ.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Disseminated Intravascular Coagulation/prevention & control , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Autophagy/drug effects , Autophagy/genetics , Betacoronavirus/growth & development , Betacoronavirus/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disseminated Intravascular Coagulation/virology , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunologic Factors/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Virus Internalization/drug effects , Virus Replication/drug effects
13.
ACS Nano ; 14(8): 10616-10623, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-696515

ABSTRACT

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/genetics , Binding Sites/genetics , Drug Design , Host Microbial Interactions/drug effects , Humans , Molecular Dynamics Simulation , Mutation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Protein Binding/drug effects , Protein Binding/genetics , Protein Binding/physiology , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
14.
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
15.
Am J Physiol Heart Circ Physiol ; 319(3): H604-H609, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-696288

ABSTRACT

Coronavirus disease 2019 (COVID-19) and diabetes outcomes (CORONADO) trial revealed that 10.6% of patients with diabetes mellitus hospitalized for COVID-19 (COVID-19) die within 7 days. Several studies from New York, Italy, and China confirm that patients with diabetes are at a much higher risk for mortality due to COVID-19. Besides respiratory illness, COVID-19 increases cardiac injury and diabetic ketoacidosis. In the absence of specific guidelines for the prevention and treatment of COVID-19 for patients with diabetes, they remain at higher risk and are more susceptible to COVID-19. Furthermore, there is a scarcity of basic knowledge on how diabetes affects pathogenesis of severe acute respiratory coronavirus (SARS-CoV-2) infection. In patients with diabetes, impaired glucose use alters metabolic and consequently biological processes instigating pathological remodeling, which has detrimental effects on cardiovascular systems. A majority of biological processes are regulated by noncoding microRNAs (miRNAs), which have emerged as a promising therapeutic candidate for several diseases. In consideration of the higher risk of mortality in patients with diabetes and COVID-19, novel diagnostic test and treatment strategy are urgently warranted in post-COVID-19 era. Here, we describe potential roles of miRNA as a biomarker and therapeutic candidate, especially for heart failure, in patients with diabetes and COVID-19.


Subject(s)
Coronavirus Infections/metabolism , Diabetes Complications/epidemiology , MicroRNAs/genetics , Pneumonia, Viral/metabolism , Animals , Biomarkers/metabolism , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Humans , MicroRNAs/metabolism , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology
16.
PLoS One ; 15(8): e0237295, 2020.
Article in English | MEDLINE | ID: covidwho-695314

ABSTRACT

We develop fully glycosylated computational models of ACE2-Fc fusion proteins which are promising targets for a COVID-19 therapeutic. These models are tested in their interaction with a fragment of the receptor-binding domain (RBD) of the Spike Protein S of the SARS-CoV-2 virus, via atomistic molecular dynamics simulations. We see that some ACE2 glycans interact with the S fragments, and glycans are influencing the conformation of the ACE2 receptor. Additionally, we optimize algorithms for protein glycosylation modelling in order to expedite future model development. All models and algorithms are openly available.


Subject(s)
Betacoronavirus/metabolism , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Algorithms , Betacoronavirus/isolation & purification , Binding Sites , Coronavirus Infections/pathology , Coronavirus Infections/virology , Glycosylation , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Structure, Tertiary , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism
17.
Open Biol ; 10(8): 200162, 2020 08.
Article in English | MEDLINE | ID: covidwho-694802

ABSTRACT

While initially recognized as causing respiratory disease, the SARS-CoV-2 virus also affects many other organs leading to other complications. It has emerged that advanced age and obesity are risk factors for complications but questions concerning the potential effects on fetal health and successful pregnancy for those infected with SARS-CoV-2 remain largely unanswered. Here, we examine human pre-gastrulation embryos to determine the expression patterns of the genes ACE2, encoding the SARS-CoV-2 receptor, and TMPRSS2, encoding a protease that cleaves both the viral spike protein and the ACE2 receptor to facilitate infection. We show expression and co-expression of these genes in the trophoblast of the blastocyst and syncytiotrophoblast and hypoblast of the implantation stages, which develop into tissues that interact with the maternal blood supply for nutrient exchange. Expression of ACE2 and TMPRSS2 in these tissues raises the possibility for vertical transmission and indicates that further work is required to understand potential risks to implantation, placental health and fetal health that require further study.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/pathology , Embryo, Mammalian/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Serine Endopeptidases/metabolism , Betacoronavirus/isolation & purification , Coronavirus Infections/transmission , Coronavirus Infections/virology , Female , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Pregnancy , Pregnancy Trimester, First , Serine Endopeptidases/genetics , Single-Cell Analysis , Trophoblasts/metabolism
18.
Int J Environ Res Public Health ; 17(15)2020 08 02.
Article in English | MEDLINE | ID: covidwho-693532

ABSTRACT

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists -coping with the high inter-individual variability of COVID-19, and for policy makers -coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM)2.5 concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February-31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM2.5 levels and the incidence (r = 0.67, p < 0.0001), the mortality rate (r = 0.65, p < 0.0001) and the case fatality rate (r = 0.7, p < 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.


Subject(s)
Air Pollution/adverse effects , Coronavirus Infections/virology , Particulate Matter/adverse effects , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Base Sequence , Betacoronavirus , Coronavirus Infections/epidemiology , Humans , Italy/epidemiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Promoter Regions, Genetic , Receptors, Virus/genetics , Up-Regulation
19.
PLoS One ; 15(7): e0235987, 2020.
Article in English | MEDLINE | ID: covidwho-690896

ABSTRACT

Development of novel approaches for regulating the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) is becoming increasingly important within the context of the ongoing COVID-19 pandemic since these enzymes play a crucial role in cell infection. In this work we searched for putative ACE2 and TMPRSS2 expression regulation networks mediated by various miRNA isoforms (isomiR) across different human organs using publicly available paired miRNA/mRNA-sequencing data from The Cancer Genome Atlas (TCGA) project. As a result, we identified several miRNA families targeting ACE2 and TMPRSS2 genes in multiple tissues. In particular, we found that lysine-specific demethylase 5B (JARID1B), encoded by the KDM5B gene, can indirectly affect ACE2 / TMPRSS2 expression by repressing transcription of hsa-let-7e / hsa-mir-125a and hsa-mir-141 / hsa-miR-200 miRNA families which are targeting these genes.


Subject(s)
Betacoronavirus , Coronavirus Infections/enzymology , Gene Expression Regulation , MicroRNAs/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/enzymology , RNA, Messenger/genetics , Serine Endopeptidases/genetics , 3' Untranslated Regions , Coronavirus Infections/virology , Databases, Genetic , Gene Regulatory Networks , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , MicroRNAs/metabolism , Nuclear Proteins/genetics , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , RNA Isoforms/genetics , RNA, Messenger/metabolism , RNA-Seq , Repressor Proteins/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis
20.
Am J Physiol Endocrinol Metab ; 319(3): E562-E567, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-690332

ABSTRACT

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delaying viral clearance in men as compared with women. We propose that modulating sex hormones, either by increasing estrogen or antiandrogen, may be a therapeutic option to reduce mortality from SARS-CoV-2.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/mortality , Gonadal Steroid Hormones/physiology , Pneumonia, Viral/mortality , Sex Characteristics , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/virology , Estradiol/metabolism , Estradiol/pharmacology , Female , Gene Expression Regulation/drug effects , Humans , Male , Mortality , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Renin-Angiotensin System/drug effects , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Sex Factors , Viral Load/drug effects , Viral Load/genetics
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