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1.
Emerg Microbes Infect ; 9(1): 1567-1579, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32602823

RESUMO

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).


Assuntos
Betacoronavirus/fisiologia , Quirópteros/virologia , Proteínas de Membrana/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores Virais/metabolismo , Serina Endopeptidases/metabolismo , Internalização do Vírus , Animais , Betacoronavirus/classificação , Células HEK293 , Humanos , Ratos , Vírus da SARS/fisiologia , Viverridae
2.
Fertil Steril ; 114(1): 33-43, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32622411

RESUMO

OBJECTIVE: To identify cell types in the male and female reproductive systems at risk for SARS-CoV-2 infection because of the expression of host genes and proteins used by the virus for cell entry. DESIGN: Descriptive analysis of transcriptomic and proteomic data. SETTING: Academic research department and clinical diagnostic laboratory. PATIENT(S): Not applicable (focus was on previously generated gene and protein expression data). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of cell types coexpressing the key angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) genes and proteins as well as other candidates potentially involved in SARS-CoV-2 cell entry. RESULT(S): On the basis of single-cell RNA sequencing data, coexpression of ACE2 and TMPRSS2 was not detected in testicular cells, including sperm. A subpopulation of oocytes in nonhuman primate ovarian tissue was found to express ACE2 and TMPRSS2, but coexpression was not observed in ovarian somatic cells. RNA expression of TMPRSS2 in 18 samples of human cumulus cells was shown to be low or absent. There was general agreement between publicly available bulk RNA and protein datasets in terms of ACE2 and TMPRSS2 expression patterns in testis, ovary, endometrial, and placental cells. CONCLUSION(S): These analyses suggest that SARS-CoV-2 infection is unlikely to have long-term effects on male and female reproductive function. Although the results cannot be considered definitive, they imply that procedures in which oocytes are collected and fertilized in vitro are associated with very little risk of viral transmission from gametes to embryos and may indeed have the potential to minimize exposure of susceptible reproductive cell types to infection in comparison with natural conception.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Fertilidade/fisiologia , Regulação Viral da Expressão Gênica/fisiologia , Pneumonia Viral/metabolismo , Reprodução/fisiologia , Internalização do Vírus , Adolescente , Adulto , Animais , Betacoronavirus/genética , Linhagem Celular , Infecções por Coronavirus/genética , Feminino , Humanos , Macaca fascicularis , Masculino , Ovário/citologia , Ovário/metabolismo , Ovário/virologia , Pandemias , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Gravidez , Proteômica/métodos , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Testículo/citologia , Testículo/metabolismo , Testículo/virologia , Transcriptoma/fisiologia , Adulto Jovem
3.
Commun Biol ; 3(1): 374, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641750

RESUMO

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Neoplasias da Próstata/epidemiologia , Distribuição por Sexo , Antineoplásicos Hormonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Betacoronavirus/ultraestrutura , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Reposicionamento de Medicamentos , Feminino , Previsões , Hormônios Esteroides Gonadais/fisiologia , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Inibidores de Proteases/uso terapêutico , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Fatores de Risco , Serina Endopeptidases/biossíntese , Serina Endopeptidases/fisiologia , Estados Unidos/epidemiologia , Internalização do Vírus
4.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641705
5.
Biochem Biophys Res Commun ; 529(2): 263-269, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32703421

RESUMO

The World Health Organization recently announced that pandemic status has been achieved for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exponential increases in patient numbers have been reported around the world, along with proportional increases in the number of COVID-19-related deaths. The SARS-CoV-2 infection rate in a population is expected to be influenced by social practices, availability of vaccines or prophylactics, and the prevalence of susceptibility genes in the population. Previous work revealed that cellular uptake of SARS-CoV-2 requires Angiotensin Converting Enzyme 2 (ACE-2) and a cellular protease. The spike (S) protein on SARS-CoV-2 binds ACE-2, which functions as an entry receptor. Following receptor binding, transmembrane protease serine 2 (encoded by TMPRSS2) primes the S protein to allow cellular uptake. Therefore, individual expression of TMPRSS2 may be a crucial determinant of SARS-CoV-2 infection susceptibility. Here, we utilized multiple large genome databases, including the GTEx portal, SNP nexus, and Ensembl genome project, to identify gene expression profiles for TMPRSS2 and its important expression quantitative trait loci. Our results show that four variants (rs464397, rs469390, rs2070788 and rs383510) affect expression of TMPRSS2 in lung tissue. The allele frequency of each variant was then assessed in regional populations, including African, American, European, and three Asian cohorts (China, Japan and Taiwan). Interestingly, our data shows that TMPRSS2-upregulating variants are at higher frequencies in European and American populations than in the Asian populations, which implies that these populations might be relatively susceptible to SARS-CoV-2 infection.


Assuntos
Betacoronavirus/metabolismo , Regulação da Expressão Gênica/genética , Internacionalidade , Pulmão/metabolismo , Receptores Virais/genética , Serina Endopeptidases/genética , Ásia/etnologia , Estudos de Coortes , Europa (Continente)/etnologia , Frequência do Gene , Genética Populacional , Mapeamento Geográfico , Humanos , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Estados Unidos/etnologia , Regulação para Cima/genética
6.
J Bone Joint Surg Am ; 102(14): 1197-1204, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32675661

RESUMO

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients who become infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some patients develop severe symptoms that can permanently detract from their quality of life. SARS-CoV-2 is closely related to SARS-CoV-1, which causes severe acute respiratory syndrome (SARS). Both viruses infect the respiratory system, and there are direct and indirect effects of this infection on multiple organ systems, including the musculoskeletal system. Epidemiological data from the SARS pandemic of 2002 to 2004 identified myalgias, muscle dysfunction, osteoporosis, and osteonecrosis as common sequelae in patients with moderate and severe forms of this disease. Early studies have indicated that there is also considerable musculoskeletal dysfunction in some patients with COVID-19, although long-term follow-up studies have not yet been conducted. The purpose of this article was to summarize the known musculoskeletal pathologies in patients with SARS or COVID-19 and to combine this with computational modeling and biochemical signaling studies to predict musculoskeletal cellular targets and long-term consequences of the SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/complicações , Sistema Musculoesquelético/fisiopatologia , Pneumonia Viral/complicações , Betacoronavirus , Osso e Ossos/fisiopatologia , Simulação por Computador , Humanos , Articulações/fisiopatologia , Debilidade Muscular/virologia , Músculo Esquelético/fisiopatologia , Mialgia/virologia , Pandemias , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética
7.
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
8.
BMC Med ; 18(1): 216, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32664879

RESUMO

BACKGROUND: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown. MAIN BODY: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19. CONCLUSION: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.


Assuntos
Infecções por Coronavirus/genética , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Grupo com Ancestrais do Continente Africano , Betacoronavirus , Infecções por Coronavirus/etnologia , Genética Populacional , Humanos , Masculino , Pandemias , Pneumonia Viral/etnologia , Polimorfismo Genético , Locos de Características Quantitativas , Fatores de Risco
9.
Aging (Albany NY) ; 12(11): 10087-10098, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501810

RESUMO

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of COVID-19 severity among Italians by looking at expression levels and variants in ACE2 and TMPRSS2 genes, crucial for viral infection.Exome and SNP-array data from a large Italian cohort were used to compare the rare-variants burden and polymorphisms frequency with Europeans and East Asians. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.While we found no significant evidence that ACE2 is associated with disease severity/sex bias, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, prompting for rapid experimental validations on large patient cohorts.


Assuntos
Infecções por Coronavirus/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/metabolismo
10.
Endocr Relat Cancer ; 27(9): R281-R292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32508311

RESUMO

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/etiologia , Pneumonia Viral/etiologia , Neoplasias da Próstata/tratamento farmacológico , Androgênios/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Serina Endopeptidases/fisiologia
11.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532094

RESUMO

Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 mM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat's safety, make it a likely candidate drug to treat COVID-19.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Guanidinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/metabolismo , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Gabexato/análogos & derivados , Gabexato/farmacologia , Células HEK293 , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
12.
Genes (Basel) ; 11(6)2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545271

RESUMO

There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing ACE2 and TMPRSS2. Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection.


Assuntos
Betacoronavirus/metabolismo , Enterócitos/metabolismo , Trato Gastrointestinal Inferior/metabolismo , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Sequência de Bases , Células Cultivadas , Infecções por Coronavirus/patologia , Enterócitos/virologia , Gastroenteropatias/virologia , Humanos , Trato Gastrointestinal Inferior/virologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Análise de Sequência , Serina Endopeptidases/metabolismo , Internalização do Vírus
13.
Fertil Steril ; 113(6): 1135-1139, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32482249

RESUMO

OBJECTIVE: To describe detection of severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) in seminal fluid of patients recovering from coronavirus disease 2019 (COVID-19) and to describe the expression profile of angiotensin-converting enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) within the testicle. DESIGN: Observational, cross-sectional study. SETTING: Tertiary referral center. PATIENT(S): Thirty-four adult Chinese males diagnosed with COVID-19 through confirmatory quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) from pharyngeal swab samples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of SARS-CoV-2 on qRT-PCR of single ejaculated semen samples. Semen quality was not assessed. Expression patterns of ACE2 and TMPRSS2 in the human testis are explored through previously published single-cell transcriptome datasets. RESULT(S): Six patients (19%) demonstrated scrotal discomfort suggestive of viral orchitis around the time of COVID-19 confirmation. Severe acute respiratory syndrome-CoV-2 was not detected in semen after a median of 31 days (interquartile range, 29-36 days) from COVID-19 diagnosis. Single-cell transcriptome analysis demonstrates sparse expression of ACE2 and TMPRSS2, with almost no overlapping gene expression. CONCLUSION(S): Severe acute respiratory syndrome-CoV-2 was not detected in the semen of patients recovering from COVID-19 1 month after COVID-19 diagnosis. Angiotensin-converting enzyme 2-mediated viral entry of SARS-CoV-2 into target host cells is unlikely to occur within the human testicle based on ACE2 and TMPRSS2 expression. The long-term effects of SARS-CoV-2 on male reproductive function remain unknown.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Sêmen/virologia , Adolescente , Adulto , Betacoronavirus/genética , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/genética , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/diagnóstico , Pneumonia Viral/enzimologia , Pneumonia Viral/genética , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Serina Endopeptidases/genética , Testículo/enzimologia , Testículo/virologia , Fatores de Tempo , Transcriptoma , Internalização do Vírus , Adulto Jovem
14.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L39-L44, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491949

RESUMO

The rapid emergence and subsequent global dissemination of SARS-CoV-2 disease (COVID-19) has resulted in over 4 million cases worldwide. The disease has a marked predilection for adults, and children are relatively spared. Understanding the age-based differences in pathophysiological pathways and processes relevant to the onset and progression of disease both in the clinical course and in experimental disease models may hold the key to the identification of therapeutic targets. The differences in the clinical course are highlighted by the lack of progression of the SARS-CoV-2 infection beyond mild symptoms in a majority of children, whereas in adults the disease progresses to acute lung injury and an acute respiratory distress syndrome (ARDS)-like phenotype with high mortality. The pathophysiological mechanisms leading to decreased lung injury in children may involve the decreased expression of the mediators necessary for viral entry into the respiratory epithelium and differences in the immune system responses in children. Specifically, decreased expression of proteins, including angiotensin-converting enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) in the airway epithelium in children may prevent viral entry. The immune system differences may include a relative preponderance of CD4+ T cells, decreased neutrophil infiltration, decreased production of proinflammatory cytokines, and increased production of immunomodulatory cytokines in children compared with adults. Notably, the developing lung in children may have a greater capacity to recover and repair after viral infection. Understanding the relative contributions of the above processes to the protective phenotype in the developing lung can guide the trial of the appropriate therapies in adults.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Adulto , Distribuição por Idade , Criança , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Citocinas/sangue , Humanos , Pandemias , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo
15.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 221-229, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32538775

RESUMO

It can be misleading to think that the new severe acute respiratory syndrome coronavirus (SARS-CoV2) which has a very strong mutation and adaptation capabilities, uses only the angiotensin-converting enzyme II (ACE2) pathway to reach target cells. Despite all the precautions taken, the pandemic attack continues and the rapid increase in the number of deaths suggest that this virus has entered the cell through different pathways and caused damage through different mechanisms. The main reason why the ACE2 pathway comes to the fore in all scientific studies is that this receptor is located at the entry point of basic mechanisms that provide alveolo-capillary homeostasis. SARS-CoV-2 has to use nuclear factor-κB (NF-kB), caveloae, clathrin, lipoxin, serine protease and proteasome pathways in addition to ACE2 to enter the target cell and initiate damage. For this reason, while new drug development studies are continuing, in order to be beneficial to patients in their acute period, it is imperative that we are able to come up with drugs that activate or inhibit these pathways and are currently in clinical use. It is also critical that we adopt these new pathways to the treatment of pregnant women affected by SARS-CoV-2, based on the scientific data we use to treat the general population.


Assuntos
Betacoronavirus/metabolismo , Caveolina 1/metabolismo , Infecções por Coronavirus/metabolismo , Lipoxinas/metabolismo , NF-kappa B/metabolismo , Pneumonia Viral/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , NF-kappa B/antagonistas & inibidores , Uso Off-Label , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Inibidores de Proteassoma/uso terapêutico , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/uso terapêutico , Internalização do Vírus
16.
PLoS One ; 15(6): e0235106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574196

RESUMO

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has devastated health infrastructure around the world. Both ACE2 (an entry receptor) and TMPRSS2 (used by the virus for spike protein priming) are key proteins to SARS-CoV-2 cell entry, enabling progression to COVID-19 in humans. Comparative genomic research into critical ACE2 binding sites, associated with the spike receptor binding domain, has suggested that African and Asian primates may also be susceptible to disease from SARS-CoV-2 infection. Savanna monkeys (Chlorocebus spp.) are a widespread non-human primate with well-established potential as a bi-directional zoonotic/anthroponotic agent due to high levels of human interaction throughout their range in sub-Saharan Africa and the Caribbean. To characterize potential functional variation in savanna monkey ACE2 and TMPRSS2, we inspected recently published genomic data from 245 savanna monkeys, including 163 wild monkeys from Africa and the Caribbean and 82 captive monkeys from the Vervet Research Colony (VRC). We found several missense variants. One missense variant in ACE2 (X:14,077,550; Asp30Gly), common in Ch. sabaeus, causes a change in amino acid residue that has been inferred to reduce binding efficiency of SARS-CoV-2, suggesting potentially reduced susceptibility. The remaining populations appear as susceptible as humans, based on these criteria for receptor usage. All missense variants observed in wild Ch. sabaeus populations are also present in the VRC, along with two splice acceptor variants (at X:14,065,076) not observed in the wild sample that are potentially disruptive to ACE2 function. The presence of these variants in the VRC suggests a promising model for SARS-CoV-2 infection and vaccine and therapy development. In keeping with a One Health approach, characterizing actual susceptibility and potential for bi-directional zoonotic/anthroponotic transfer in savanna monkey populations may be an important consideration for controlling COVID-19 epidemics in communities with frequent human/non-human primate interactions that, in many cases, may have limited health infrastructure.


Assuntos
Chlorocebus aethiops , Infecções por Coronavirus/veterinária , Pandemias/veterinária , Peptidil Dipeptidase A/genética , Pneumonia Viral/veterinária , Doenças dos Primatas/genética , Serina Endopeptidases/genética , Animais , Betacoronavirus/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Suscetibilidade a Doenças , Pneumonia Viral/genética , Pneumonia Viral/transmissão , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequenciamento Completo do Genoma , Zoonoses/transmissão
17.
J Transl Med ; 18(1): 257, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586380

RESUMO

BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.


Assuntos
Betacoronavirus/fisiologia , Biologia Computacional , Infecções por Coronavirus/genética , Infecções por Coronavirus/terapia , Pneumonia Viral/genética , Pneumonia Viral/terapia , Animais , Betacoronavirus/genética , Regulação da Expressão Gênica , Glutamina/metabolismo , Humanos , Camundongos , Pandemias , Peptidil Dipeptidase A/metabolismo , Serina Endopeptidases/metabolismo
18.
Cell ; 182(2): 429-446.e14, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32526206

RESUMO

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistema Respiratório/virologia , Genética Reversa/métodos , Idoso , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Linhagem Celular , Células Cultivadas , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Fibrose Cística/patologia , DNA Recombinante , Feminino , Furina/metabolismo , Humanos , Imunização Passiva , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Mucosa Nasal/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Sistema Respiratório/patologia , Serina Endopeptidases/metabolismo , Células Vero , Virulência , Replicação Viral
19.
Am J Physiol Cell Physiol ; 319(2): C244-C249, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32515982

RESUMO

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Sulfeto de Hidrogênio/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Sulfeto de Hidrogênio/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Transdução de Sinais
20.
Eye (Lond) ; 34(7): 1212-1219, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32382146

RESUMO

PURPOSE: To determine the expressions of SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) genes in human and mouse ocular cells and comparison to other tissue cells. METHODS: Human conjunctiva and primary pterygium tissues were collected from pterygium patients who underwent surgery. The expression of ACE2 and TMPRSS2 genes was determined in human primary conjunctival and pterygium cells, human ocular and other tissue cell lines, mesenchymal stem cells as well as mouse ocular and other tissues by reverse transcription-polymerase chain reaction (RT-PCR) and SYBR green PCR. RESULTS: RT-PCR analysis showed consistent expression by 2 ACE2 gene primers in 2 out of 3 human conjunctival cells and pterygium cell lines. Expression by 2 TMPRSS2 gene primers could only be found in 1 out of 3 pterygium cell lines, but not in any conjunctival cells. Compared with the lung A549 cells, similar expression was noted in conjunctival and pterygium cells. In addition, mouse cornea had comparable expression of Tmprss2 gene and lower but prominent Ace2 gene expression compared with the lung tissue. CONCLUSION: Considering the necessity of both ACE2 and TMPRSS2 for SARS-CoV-2 infection, our results suggest that conjunctiva would be less likely to be infected by SARS-CoV-2, whereas pterygium possesses some possibility of SARS-CoV-2 infection. With high and consistent expression of Ace2 and Tmprss2 in cornea, cornea rather than conjunctiva has higher potential to be infected by SARS-CoV-2. Precaution is necessary to prevent possible SARS-CoV-2 infection through ocular surface in clinical practice.


Assuntos
Betacoronavirus/metabolismo , Túnica Conjuntiva/anormalidades , Túnica Conjuntiva/metabolismo , Infecções por Coronavirus , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Pterígio/metabolismo , Serina Endopeptidases/metabolismo , Animais , Betacoronavirus/enzimologia , Betacoronavirus/genética , Linhagem Celular , Córnea , Humanos , Pulmão/metabolismo , Camundongos
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