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1.
Redox Biol ; 36: 101615, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32863223

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in hundreds of thousands of deaths worldwide. While the majority of people with COVID-19 won't require hospitalization, those who do may experience severe life-threatening complications, including acute respiratory distress syndrome. SARS-CoV-2 infects human cells by binding to the cellular surface protein angiotensin-converting enzyme 2 (ACE2); in addition, the cellular transmembrane serine protease 2 (TMPRSS2) is needed for priming of the spike (S) protein of the virus. Virus entry may also depend on the activity of the endosomal/lysosomal cysteine proteases cathepsin B, L (CTSB, CTSL) although their activity is likely dispensable. Given that the uncertainty of how COVID-19 kills, hampers doctors' ability to choose treatments the need for a deep understanding of COVID-19 biology is urgent. Herein, we performed an expression profiling meta-analysis of ACE2, TMPRSS2 and CTSB/L genes (and proteins) in public repository databases and found that all are widely expressed in human tissues; also, the ACE2 and TMPRSS2 genes tend to be co-regulated. The ACE2 and TMPRSS genes expression is (among others) suppressed by TNF, and is induced by pro-inflammatory conditions including obesity, Barrett's esophagus, stomach infection by helicobacter pylori, diabetes, autoimmune diseases and oxidized LDL; by exercise, as well as by growth factors, viruses' infections, cigarette smoke, interferons and androgens. Regarding currently investigated therapies interferon-beta induced ACE2 gene expression in bronchial epithelial cells, while chloroquine tends to upregulate CTSB/L genes. Finally, we analyzed KEGG pathways modulated by ACE2, TMPRSS2 and CTSB/L and probed DrugBank for drugs that target modules of the affected pathways. Our data indicate possible novel high-risk groups for COVID-19; provide a rich resource for future investigations of its pathogenesis and highlight the therapeutic challenges we face.


Assuntos
Betacoronavirus/fisiologia , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Catepsinas/genética , Catepsinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Peptidil Dipeptidase A/metabolismo , Mucosa Respiratória/metabolismo , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Internalização do Vírus/efeitos dos fármacos
2.
Genes (Basel) ; 11(9)2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867305

RESUMO

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.


Assuntos
Basigina/genética , Infecções por Coronavirus/genética , Furina/genética , Mutação , Pneumonia Viral/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Polimorfismo de Nucleotídeo Único
3.
Cell Rep ; 32(12): 108175, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32946807

RESUMO

To predict the tropism of human coronaviruses, we profile 28 SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) using single-cell transcriptomics across various healthy human tissues. SCARFs include cellular factors both facilitating and restricting viral entry. Intestinal goblet cells, enterocytes, and kidney proximal tubule cells appear highly permissive to SARS-CoV-2, consistent with clinical data. Our analysis also predicts non-canonical entry paths for lung and brain infections. Spermatogonial cells and prostate endocrine cells also appear to be permissive to SARS-CoV-2 infection, suggesting male-specific vulnerabilities. Both pro- and anti-viral factors are highly expressed within the nasal epithelium, with potential age-dependent variation, predicting an important battleground for coronavirus infection. Our analysis also suggests that early embryonic and placental development are at moderate risk of infection. Lastly, SCARF expression appears broadly conserved across a subset of primate organs examined. Our study establishes a resource for investigations of coronavirus biology and pathology.


Assuntos
Infecções por Coronavirus/patologia , Mucosa Nasal/metabolismo , Pneumonia Viral/patologia , Receptores Virais/genética , Tropismo Viral/genética , Internalização do Vírus , Células A549 , Animais , Betacoronavirus/crescimento & desenvolvimento , Linhagem Celular , Chlorocebus aethiops , Enterócitos/metabolismo , Perfilação da Expressão Gênica , Células Caliciformes/metabolismo , Células HEK293 , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Mucosa Nasal/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Análise de Célula Única , Células Vero
4.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L670-L674, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32878480

RESUMO

The severity of coronavirus disease 2019 (COVID-19) is linked to an increasing number of risk factors, including exogenous (environmental) stimuli such as air pollution, nicotine, and cigarette smoke. These three factors increase the expression of angiotensin I converting enzyme 2 (ACE2), a key receptor involved in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the etiological agent of COVID-19-into respiratory tract epithelial cells. Patients with severe COVID-19 are managed with oxygen support, as are at-risk individuals with chronic lung disease. To date, no study has examined whether an increased fraction of inspired oxygen (FiO2) may affect the expression of SARS-CoV-2 entry receptors and co-receptors, including ACE2 and the transmembrane serine proteases TMPRSS1, TMPRSS2, and TMPRSS11D. To address this, steady-state mRNA levels for genes encoding these SARS-CoV-2 receptors were assessed in the lungs of mouse pups chronically exposed to elevated FiO2, and in the lungs of preterm-born human infants chronically managed with an elevated FiO2. These two scenarios served as models of chronic elevated FiO2 exposure. Additionally, SARS-CoV-2 receptor expression was assessed in primary human nasal, tracheal, esophageal, bronchial, and alveolar epithelial cells, as well as primary mouse alveolar type II cells exposed to elevated oxygen concentrations. While gene expression of ACE2 was unaffected, gene and protein expression of TMPRSS11D was consistently upregulated by exposure to an elevated FiO2. These data highlight the need for further studies that examine the relative contribution of the various viral co-receptors on the infection cycle, and point to oxygen supplementation as a potential risk factor for COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Proteínas de Membrana/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Mucosa Respiratória/metabolismo , Serina Endopeptidases/metabolismo , Serina Proteases/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Betacoronavirus , Células Cultivadas , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/administração & dosagem , Oxigênio/análise , Pandemias , Receptores Virais/metabolismo , Fatores de Risco , Serina Endopeptidases/genética , Serina Proteases/genética , Índice de Gravidade de Doença
5.
ACS Chem Neurosci ; 11(19): 2944-2961, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32870641

RESUMO

A significant proportion of people who test positive for COVID-19 have chemosensory deficits. However, the reported prevalence of these deficits in smell and taste varies widely, and the reason for the differences between studies is unclear. We determined the pooled prevalence of such chemosensory deficits in a systematic review and meta-analysis. We searched the COVID-19 portfolio of the National Institutes of Health for studies that reported the prevalence of smell or taste deficits or both in patients diagnosed with COVID-19. One-hundred-four studies reporting on 38 198 patients qualified and were subjected to a systematic review and meta-analysis. Estimated random prevalence of olfactory dysfunction was 43.0%, that of taste dysfunction was 44.6%, and that of overall chemosensory dysfunction was 47.4%. We examined the effects of age, gender, disease severity, and ethnicity on chemosensory dysfunction. Prevalence of smell or taste dysfunction or both decreased with older age, male gender, and disease severity. Ethnicity was highly significant: Caucasians had a three times higher prevalence of chemosensory dysfunctions (54.8%) than Asians (17.7%). The finding of geographic differences points to two causes that are not mutually exclusive. A virus mutation (D614G) may cause differing infectivity, while at the host level genetic, ethnicity-specific variants of the virus-binding entry proteins may facilitate virus entry in the olfactory epithelium and taste buds. Both explanations have major implications for infectivity, diagnosis, and management of the COVID-19 pandemic.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Infecções por Coronavirus/fisiopatologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Transtornos do Olfato/etnologia , Pneumonia Viral/fisiopatologia , Fatores Etários , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Grupos Étnicos , Variação Genética , Humanos , Transtornos do Olfato/epidemiologia , Transtornos do Olfato/fisiopatologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Prevalência , Serina Endopeptidases/genética , Índice de Gravidade de Doença , Fatores Sexuais
6.
Sci Adv ; 6(31)2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32937591

RESUMO

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.


Assuntos
Infecções por Coronavirus/patologia , Transtornos do Olfato/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Serina Endopeptidases/metabolismo , Olfato/fisiologia , Animais , Betacoronavirus/fisiologia , Callithrix , Humanos , Macaca , Camundongos , Transtornos do Olfato/genética , Mucosa Olfatória/citologia , Mucosa Olfatória/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Pandemias , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Olfato/genética , Internalização do Vírus
7.
Sci Rep ; 10(1): 15917, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985513

RESUMO

SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor, and TMPRSS2 and Furin proteases usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret, mouse, hamster and macaque. Here we showed that ACE2, but not TMPRSS2 or Furin, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Using molecular docking simulations we compared the SARS-CoV and SARS-CoV-2 Spike proteins in complex with the ACE2 receptor and showed that the SARS-CoV-2 Spike glycoprotein is compatible to bind the human ACE2 with high specificity. In contrast, TMPRSS2 and Furin are sufficiently similar in the considered hosts not to drive susceptibility differences. Computational analysis of binding modes and protein contacts indicates that macaque, ferrets and hamster are the most suitable models for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 and Furin are similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are also likely to be useful models for studies investigating viral entry.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/veterinária , Pandemias/veterinária , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/veterinária , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos/genética , Animais , Gatos , Biologia Computacional/métodos , Infecções por Coronavirus/patologia , Cricetinae , Modelos Animais de Doenças , Cães , Furões , Furina/genética , Furina/metabolismo , Cobaias , Humanos , Macaca fascicularis , Camundongos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Coelhos , Ratos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
8.
Respir Res ; 21(1): 252, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993656

RESUMO

SARS-CoV-2 is causing a pandemic with currently > 29 million confirmed cases and > 900,000 deaths worldwide. The locations and mechanisms of virus entry into the human respiratory tract are incompletely characterized. We analyzed publicly available RNA microarray datasets for SARS-CoV-2 entry receptors and cofactors ACE2, TMPRSS2, BSG (CD147) and FURIN. We found that ACE2 and TMPRSS2 are upregulated in the airways of smokers. In asthmatics, ACE2 tended to be downregulated in nasal epithelium, and TMPRSS2 was upregulated in the bronchi. Furthermore, respiratory epithelia were negative for ACE-2 and TMPRSS2 protein expression while positive for BSG and furin, suggesting a possible alternative entry route for SARS-CoV-2.


Assuntos
Asma/virologia , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Pneumonia Viral/genética , Serina Endopeptidases/genética , Síndrome Respiratória Aguda Grave/virologia , Fumar/epidemiologia , Asma/fisiopatologia , Bases de Dados Factuais , Humanos , Pandemias , Receptores Virais/genética , Valores de Referência , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/metabolismo , Fumar/fisiopatologia , Internalização do Vírus
9.
Emerg Microbes Infect ; 9(1): 2169-2179, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969768

RESUMO

Studies on patients with the coronavirus disease-2019 (COVID-19) have implicated that the gastrointestinal (GI) tract is a major site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We established a human GI tract cell line model highly permissive to SARS-CoV-2. These cells, C2BBe1 intestinal cells with a brush border having high levels of transmembrane serine protease 2 (TMPRSS2), showed robust viral propagation, and could be persistently infected with SARS-CoV-2, supporting the clinical observations of persistent GI infection in COVID-19 patients. Ectopic expression of viral receptors revealed that the levels of angiotensin-converting enzyme 2 (ACE2) expression confer permissiveness to SARS-CoV-2 infection, and TMPRSS2 greatly facilitates ACE2-mediated SARS-CoV-2 dissemination. Interestingly, ACE2 but not TMPRSS2 expression was significantly promoted by enterocytic differentiation, suggesting that the state of enterocytic differentiation may serve as a determining factor for viral propagation. Thus, our study sheds light on the pathogenesis of SARS-CoV-2 in the GI tract.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Mucosa Intestinal/virologia , Pneumonia Viral/virologia , Betacoronavirus/genética , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/virologia , Humanos , Mucosa Intestinal/metabolismo , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
10.
Cell Death Dis ; 11(9): 799, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973152

RESUMO

A severe upper respiratory tract syndrome caused by the new coronavirus has now spread to the entire world as a highly contagious pandemic. The large scale explosion of the disease is conventionally traced back to January of this year in the Chinese province of Hubei, the wet markets of the principal city of Wuhan being assumed to have been the specific causative locus of the sudden explosion of the infection. A number of findings that are now coming to light show that this interpretation of the origin and history of the pandemic is overly simplified. A number of variants of the coronavirus would in principle have had the ability to initiate the pandemic well before January of this year. However, even if the COVID-19 had become, so to say, ready, conditions in the local environment would have had to prevail to induce the loss of the biodiversity's "dilution effect" that kept the virus under control, favoring its spillover from its bat reservoir to the human target. In the absence of these appropriate conditions only abortive attempts to initiate the pandemic could possibly occur: a number of them did indeed occur in China, and probably elsewhere as well. These conditions were unfortunately present at the wet marked in Wuhan at the end of last year.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , Betacoronavirus/classificação , Betacoronavirus/genética , Quirópteros/virologia , Infecções por Coronavirus/transmissão , Eutérios/virologia , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Filogenia , Pneumonia Viral/transmissão , Ligação Proteica , Vírus da SARS/classificação , Vírus da SARS/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Síndrome Respiratória Aguda Grave/transmissão , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Viverridae/virologia
12.
Open Biol ; 10(8): 200162, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32750256

RESUMO

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.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/patologia , Embrião de Mamíferos/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Serina Endopeptidases/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Primeiro Trimestre da Gravidez , Serina Endopeptidases/genética , Análise de Célula Única , Trofoblastos/metabolismo
13.
Mayo Clin Proc ; 95(9): 1989-1999, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32861340

RESUMO

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has rapidly caused a global pandemic associated with a novel respiratory infection: coronavirus disease-19 (COVID-19). Angiotensin-converting enzyme-2 (ACE2) is necessary to facilitate SARS-CoV-2 infection, but-owing to its essential metabolic roles-it may be difficult to target it in therapies. Transmembrane protease serine 2 (TMPRSS2), which interacts with ACE2, may be a better candidate for targeted therapies. Using publicly available expression data, we show that both ACE2 and TMPRSS2 are expressed in many host tissues, including lung. The highest expression of ACE2 is found in the testes, whereas the prostate displays the highest expression of TMPRSS2. Given the increased severity of disease among older men with SARS-CoV-2 infection, we address the potential roles of ACE2 and TMPRSS2 in their contribution to the sex differences in severity of disease. We show that expression levels of ACE2 and TMPRSS2 are overall comparable between men and women in multiple tissues, suggesting that differences in the expression levels of TMPRSS2 and ACE2 in the lung and other non-sex-specific tissues may not explain the gender disparities in severity of SARS CoV-2. However, given their instrumental roles for SARS-CoV-2 infection and their pleiotropic expression, targeting the activity and expression levels of TMPRSS2 is a rational approach to treat COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Serina Endopeptidases/genética , Fatores Sexuais , Betacoronavirus , Feminino , Expressão Gênica , Frequência do Gene , Humanos , Pulmão , Masculino , Pandemias , Peptidil Dipeptidase A/genética
14.
Genes Immun ; 21(4): 269-272, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32759995

RESUMO

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.


Assuntos
Infecções por Coronavirus/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/etnologia , Feminino , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/etnologia , Serina Endopeptidases/metabolismo
15.
Molecules ; 25(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842606

RESUMO

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Catepsina L/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Receptores Virais/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Expressão Gênica , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Índia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Pandemias , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Termodinâmica , Internalização do Vírus/efeitos dos fármacos
16.
DNA Cell Biol ; 39(9): 1621-1638, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758021

RESUMO

Increasing evidence highlights the clinical significance of stromal cells and immune cells in the liver cancer microenvironment. However, reliable prognostic models have not been well established. This study aimed to develop a gene signature for liver cancer based on stromal and immune scores. Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, stromal and immune scores were estimated based on the transcriptome profile of The Cancer Genome Atlas (TCGA) liver cancer cohort. Stromal-/immune-related differentially expressed genes were identified, followed by functional enrichment analysis. The Cox regression model was used to select prognostic genes and construct a gene signature. Its predictive potential was evaluated by receiver operating characteristic (ROC). The correlation between the risk score and immune cell infiltration was analyzed using Tumor Immune Estimation Resource (TIMER). Three hundred sixty-four upregulated and 10 downregulated stromal-/immune-related genes were identified, were mainly enriched in immune-related processes and pathways. Through univariate and multivariate cox survival analysis, a five-gene risk score was constructed, composed of FABP3, HTRA3, OLFML2B, PDZD4 and SLAMF6. Patients with high score indicated a poorer prognosis than those with low risk score. The areas under the ROC curves of overall survival (OS), progression-free interval, 3-, 5-year, OS status were 0.68, 0.57, 0.72, 0.74 and 0.728, indicating its well performance on predicting patients' prognoses. Furthermore, the risk score and the five genes were significantly correlated with immune cell infiltration in the tumor microenvironment. In this study, we proposed a prognostic five-gene signature based on stromal/immune scores in the liver cancer microenvironment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Hepáticas/genética , Microambiente Tumoral , Idoso , Biomarcadores Tumorais/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Proteína 3 Ligante de Ácido Graxo/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Transcriptoma
17.
Gac Med Mex ; 156(4): 354-357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831324

RESUMO

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.


Assuntos
Infecções por Coronavirus/complicações , Peptidil Dipeptidase A/genética , Pneumonia Viral/complicações , Serina Endopeptidases/genética , Dermatopatias Virais/virologia , Betacoronavirus/isolamento & purificação , Linhagem Celular , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Pandemias , Pneumonia Viral/genética , Pele/virologia , Dermatopatias Virais/genética , Tropismo Viral/fisiologia , Internalização do Vírus
18.
Gac Med Mex ; 156(4): 328-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831326

RESUMO

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.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Testículo/virologia , Basigina/genética , Infecções por Coronavirus/fisiopatologia , Regulação da Expressão Gênica , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/fisiopatologia , Serina Endopeptidases/genética , Latência Viral
19.
Infection ; 48(5): 665-669, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32737833

RESUMO

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Catepsinas/genética , Catepsinas/imunologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Ativação Enzimática/imunologia , Humanos , Evasão da Resposta Imune , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Ligação Proteica , Domínios Proteicos , Vírus da SARS/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/patologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus , Replicação Viral
20.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-32661206

RESUMO

At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age>60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein-protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 50 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/genética , Dipeptidil Peptidase 4/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/metabolismo , Epigenômica , Predisposição Genética para Doença , Variação Genética , Humanos , Desequilíbrio de Ligação , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
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