Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 100
Filtrar
2.
Emerg Microbes Infect ; 9(1): 2433-2445, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33073694

RESUMO

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1-3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Vírus da SARS/crescimento & desenvolvimento , Replicação Viral/genética , Células A549 , Adenoviridae/genética , Animais , Betacoronavirus/metabolismo , Linhagem Celular , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pandemias , Vírus da SARS/metabolismo , Células Vero , Ligação Viral
3.
Curr Protoc Microbiol ; 59(1): e126, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33048448

RESUMO

SARS-CoV-2, the causative agent of COVID-19, has been responsible for a million deaths worldwide as of September 2020. At the time of this writing, there are no available US FDA-approved therapeutics for the treatment of SARS-CoV-2 infection. Here, we describe a detailed protocol to generate recombinant (r)SARS-CoV-2 using reverse-genetics approaches based on the use of a bacterial artificial chromosome (BAC). This method will allow the production of mutant rSARS-CoV-2-which is necessary for understanding the function of viral proteins, viral pathogenesis and/or transmission, and interactions at the virus-host interface-and attenuated SARS-CoV-2 to facilitate the discovery of effective countermeasures to control the ongoing SARS-CoV-2 pandemic. © 2020 Wiley Periodicals LLC. Basic Protocol: Generation of recombinant SARS-CoV-2 using a bacterial artificial chromosome Support Protocol: Validation and characterization of rSARS-CoV-2.


Assuntos
Betacoronavirus/genética , Cromossomos Artificiais Bacterianos/genética , Animais , Betacoronavirus/crescimento & desenvolvimento , Chlorocebus aethiops , Contenção de Riscos Biológicos , Transfecção , Células Vero
4.
Afr J Prim Health Care Fam Med ; 12(1): e1-e3, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33054266

RESUMO

Early in the course of the coronavirus infection disease 2019 (COVID-19) pandemic in South Africa, the Department of Health implemented a policy of community screening and testing (CST). This was based on a community-orientated primary care approach and was a key strategy in limiting the spread of the pandemic, but it struggled with long turnaround times (TATs) for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction test. The local experience at Symphony Way Community Day Centre (Delft, Cape Town), highlighted these challenges. The first positive tests had a median TAT of 4.5 days, peaking at 29 days in mid-May 2020. Issues that contributed to long TATs were unavailability of viral transport medium, sample delivery and storage difficulties, staffing problems, scarcity of testing supplies and other samples prioritised over CST samples. At Symphony Way, many patients who tested COVID-19 positive had abandoned their self-isolation because of the delay in results. Employers were unhappy with prolonged sick leave whilst waiting for results and patients were concerned about not getting paid or job loss. The CST policy relies on a rapid TAT to be successful. Once the TAT is delayed, the process of contacting patients, and tracing and quarantining contacts becomes ineffective. With hindsight, other countries' difficulties in upscaling testing should have served as warning. Community screening and testing was scaled back from 18 May 2020, and testing policy was changed to only include high-risk patients from 29 May 2020. The delayed TATs meant that the CST policy had no beneficial impact at local level.


Assuntos
Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Acesso aos Serviços de Saúde , Programas de Rastreamento , Pneumonia Viral/diagnóstico , Políticas , Betacoronavirus/crescimento & desenvolvimento , Técnicas de Laboratório Clínico/métodos , Coronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Programas de Rastreamento/métodos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Síndrome Respiratória Aguda Grave , África do Sul , Fatores de Tempo
5.
Clin Microbiol Rev ; 34(1)2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33055231

RESUMO

Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir (GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses. In vivo, remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Doença pelo Vírus Ebola/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Alanina/farmacocinética , Alanina/farmacologia , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo/métodos , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Esquema de Medicação , Ebolavirus/efeitos dos fármacos , Ebolavirus/crescimento & desenvolvimento , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/crescimento & desenvolvimento , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Segurança do Paciente , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/crescimento & desenvolvimento , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Análise de Sobrevida , Resultado do Tratamento
6.
Antimicrob Resist Infect Control ; 9(1): 167, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121538

RESUMO

OBJECTIVES: We performed an environmental sampling study to investigate the environmental contamination of SARS-CoV-2 by COVID-19 patients with prolonged PCR positive status of clinical samples. METHODS: We sampled the air from rooms for nine COVID-19 patients with illness or positive PCR > 30 days, before and after nasopharyngeal/oropharyngeal swabbing and before and after nebulization treatment. We also sampled patients' surroundings and healthcare workers' personal protection equipment (PPE) in a non-ICU ward. SARS-CoV-2 was detected by PCR. RESULTS: Eighty-eight samples were collected from high-touch surfaces and floors in patient rooms and toilets, with only the bedsheets of two patients and one toilet positive for SARS-CoV-2. All air samples (n = 34) were negative for SARS-CoV-2. Fifty-five samples collected from PPE were all negative. CONCLUSION: Contamination of near-patient surroundings was uncommon for COVID-19 patients with prolonged PCR positive status if environmental cleaning/disinfection were performed rigorously. Airborne transmission of SARS-CoV-2 was unlikely in these non-ICU settings.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Equipamento de Proteção Individual , Pneumonia Viral/virologia , Betacoronavirus/crescimento & desenvolvimento , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Desinfecção/métodos , Microbiologia Ambiental , Monitoramento Ambiental/métodos , Pessoal de Saúde , Hospitais , Humanos , Pandemias/prevenção & controle , Quartos de Pacientes , Pneumonia Viral/diagnóstico , Reação em Cadeia da Polimerase , RNA Viral/isolamento & purificação
7.
Nat Commun ; 11(1): 5503, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127911

RESUMO

The spread of SARS-CoV-2 in Beijing before May, 2020 resulted from transmission following both domestic and global importation of cases. Here we present genomic surveillance data on 102 imported cases, which account for 17.2% of the total cases in Beijing. Our data suggest that all of the cases in Beijing can be broadly classified into one of three groups: Wuhan exposure, local transmission and overseas imports. We classify all sequenced genomes into seven clusters based on representative high-frequency single nucleotide polymorphisms (SNPs). Genomic comparisons reveal higher genomic diversity in the imported group compared to both the Wuhan exposure and local transmission groups, indicating continuous genomic evolution during global transmission. The imported group show region-specific SNPs, while the intra-host single nucleotide variations present as random features, and show no significant differences among groups. Epidemiological data suggest that detection of cases at immigration with mandatory quarantine may be an effective way to prevent recurring outbreaks triggered by imported cases. Notably, we also identify a set of novel indels. Our data imply that SARS-CoV-2 genomes may have high mutational tolerance.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Adulto , Pequim/epidemiologia , Infecções por Coronavirus/epidemiologia , Feminino , Genoma Viral , Genômica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pandemias , Filogenia , Pneumonia Viral/epidemiologia , Polimorfismo de Nucleotídeo Único , Viagem , Adulto Jovem
8.
Nat Commun ; 11(1): 5493, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127906

RESUMO

The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Betacoronavirus/genética , Betacoronavirus/crescimento & desenvolvimento , Biomarcadores/sangue , Proteína C-Reativa , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Feminino , Hospitalização , Humanos , Inflamação/sangue , Inflamação/virologia , Interleucina-6/sangue , Estudos Longitudinais , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , RNA Viral/sangue , Índice de Gravidade de Doença , Carga Viral , Viremia/sangue , Viremia/virologia
9.
Signal Transduct Target Ther ; 5(1): 220, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024075
10.
Virology ; 550: 61-69, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32882638

RESUMO

The world is in the midst of a pandemic caused by a novel coronavirus and is desperately searching for possible treatments. The antiviral remdesivir has shown some effectiveness against SARS-CoV-2 in vitro and in a recent animal study. We use data from a study of remdesivir in rhesus macaques to fit a viral kinetics model in an effort to determine the most appropriate mathematical descripton of the effect of remdesivir. We find statistically significant differences in the viral decay rate and use this to inform a possible mathematical formulation of the effect of remdesivir. Unfortunately, this model formulation suggests that the application of remdesivir will lengthen SARS-CoV-2 infections, putting into question its potential clinical benefit.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Modelos Estatísticos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Animais , Antivirais/sangue , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Inflamação , Macaca mulatta , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Carga Viral , Replicação Viral
11.
mSphere ; 5(5)2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32878932

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions within just a few months, causing severe respiratory disease and mortality. Assays to monitor SARS-CoV-2 growth in vitro depend on time-consuming and costly RNA extraction steps, hampering progress in basic research and drug development efforts. Here, we developed a simplified quantitative real-time PCR assay that bypasses viral RNA extraction steps and can monitor SARS-CoV-2 growth from a small amount of cell culture supernatants. In addition, we show that this approach is easily adaptable to numerous other RNA and DNA viruses. Using this assay, we screened the activities of a number of compounds that were predicted to alter SARS-CoV-2 entry and replication as well as HIV-1-specific drugs in a proof-of-concept study. We found that E64D (inhibitor of endosomal proteases cathepsin B and L) and apilimod (endosomal trafficking inhibitor) potently decreased the amount of SARS-CoV-2 RNA in cell culture supernatants with minimal cytotoxicity. Surprisingly, we found that the macropinocytosis inhibitor ethylisopropylamiloride (EIPA) similarly decreased SARS-CoV-2 RNA levels in supernatants, suggesting that entry may additionally be mediated by an alternative pathway. HIV-1-specific inhibitors nevirapine (a nonnucleoside reverse transcriptase inhibitor [NNRTI]), amprenavir (a protease inhibitor), and allosteric integrase inhibitor 2 (ALLINI-2) modestly inhibited SARS-CoV-2 replication, albeit the 50% inhibitory concentration (IC50) values were much higher than that required for HIV-1. Taking the data together, this simplified assay will expedite basic SARS-CoV-2 research, be amenable to mid-throughput screening assays (i.e., drug, CRISPR, small interfering RNA [siRNA], etc.), and be applicable to a broad number of RNA and DNA viruses.IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, is continuing to cause immense respiratory disease and social and economic disruptions. Conventional assays that monitor SARS-CoV-2 growth in cell culture rely on costly and time-consuming RNA extraction procedures, hampering progress in basic SARS-CoV-2 research and development of effective therapeutics. Here, we developed a simple quantitative real-time PCR assay to monitor SARS-CoV-2 growth in cell culture supernatants that does not necessitate RNA extraction and that is as accurate and sensitive as existing methods. In a proof-of-concept screen, we found that E64D, apilimod, EIPA, and remdesivir can substantially impede SARS-Cov-2 replication, providing novel insight into viral entry and replication mechanisms. In addition, we show that this approach is easily adaptable to numerous other RNA and DNA viruses. This simplified assay will undoubtedly expedite basic SARS-CoV-2 and virology research and be amenable to use in drug screening platforms to identify therapeutics against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Técnicas de Cultura de Células/métodos , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Pandemias , RNA Viral/análise , RNA Viral/isolamento & purificação , Replicação Viral/efeitos dos fármacos
12.
J Interferon Cytokine Res ; 40(10): 469-471, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32881593

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has recently emerged as a global health threat. To address this health emergency, various therapeutic approaches are currently under investigation. There is limited evidence on the effectiveness of hydroxychloroquine (HCQ) and chloroquine (CQ) as COVID-19 therapies, and thus World Health Organization (WHO) mentioned that "Current data shows that this drug does not reduce deaths among hospitalized COVID-19 patients, nor help people with mild or moderate disease." CQ and HCQ are typically used for the treatment of malaria but have been recognized for certain beneficial effects in COVID-19 patients based on some clinical outcomes from the clinical treatment of COVID-19. A standard dose of HCQ has been proven effective and less toxic than CQ in COVID-19 patients; however, a comprehensive understanding of a patient's clinical condition is necessary. Based on several hospital findings, the Food and Drug Administration (FDA) has officially cancelled the emergency use authorization for HCQ and CQ for treating hospitalized COVID-19 patients on June 15, 2020. In this review, we highlight both pros and cons of the clinical use of CQ and HCQ in COVID-19 patients.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Cloroquina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Anti-Infecciosos/efeitos adversos , Azitromicina/uso terapêutico , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Resultado do Tratamento
13.
Molecules ; 25(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987757

RESUMO

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fármacos do Sistema Respiratório/uso terapêutico , Doença Aguda , Anti-Inflamatórios/síntese química , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptídeos/síntese química , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/virologia , Fármacos do Sistema Respiratório/síntese química , Relação Estrutura-Atividade
14.
Trends Immunol ; 41(10): 856-859, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32863134

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mainly affects the lungs. Sarcoidosis is an autoinflammatory disease characterized by the diffusion of granulomas in the lungs and other organs. Here, we discuss how the two diseases might involve some common mechanistic cellular pathways around the regulation of autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Sarcoidose/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Autofagia/genética , Azitromicina/uso terapêutico , Betacoronavirus/crescimento & desenvolvimento , Cloroquina/uso terapêutico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Isoniazida/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Edema Pulmonar/epidemiologia , Edema Pulmonar/genética , Edema Pulmonar/virologia , Rifampina/uso terapêutico , Sarcoidose/epidemiologia , Sarcoidose/genética , Sarcoidose/virologia , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença
15.
Sci Adv ; 6(27)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32937441

RESUMO

COVID-19 has become a global pandemic caused by the novel coronavirus SARS-CoV-2. Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis, discovering new drugs, and developing a vaccine. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike and other genes among bat, pangolin, and human coronaviruses, suggesting similar evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2's entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2's ability to infect humans. Similar purifying selection in different host species, together with frequent recombination among coronaviruses, suggests a common evolutionary mechanism that could lead to new emerging human coronaviruses.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Recombinação Genética , Sequência de Aminoácidos , Animais , Betacoronavirus/classificação , Betacoronavirus/crescimento & desenvolvimento , Sítios de Ligação , Quirópteros/virologia , Infecções por Coronavirus/virologia , Evolução Molecular , Genoma Viral , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Filogenia , Pneumonia Viral/virologia , Estrutura Terciária de Proteína , Alinhamento de Sequência
16.
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
17.
Virus Res ; 288: 198137, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32827627

RESUMO

Several randomized controlled trials (RCTs) were conducted to investigate the effect of remdesivir for patients with COVID-19, but their results were conflicting. Thus, we conducted a network meta-analysis comparing the rate of clinical improvement among patients with COVID-19 who received 5-day course of remdesivir versus 10-day course of remdesivir versus standard care. Our network meta-analysis of 4 randomized controlled trials demonstrated that the rate of clinical improvement was significantly higher in the 5-day remdesivir group and 10-day remdesivir group compared to standard care group (OR [95% confidence interval [CI]] =1.89 [1.40-2.56], P <0.001, OR [95% CI] =1.38 [1.15-1.66], P <0.001, respectively). In addition, the rate of clinical improvement was significantly higher in the 5-day remdesivir group compared to the 10-day remdesivir group (OR [95% confidence interval [CI]] =1.37 [1.01-1.85], P =0.041). Our analysis demonstrated that the use of remdesivir for patients with COVID-19 was associated with the significantly higher clinical improvement rate compared with standard care alone.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antimetabólitos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/metabolismo , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Progressão da Doença , Esquema de Medicação , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
18.
Cytokine ; 136: 155228, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32822911

RESUMO

The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Infecções por Coronavirus/complicações , Quimioterapia Combinada , Humanos , Modelos Biológicos , Pandemias , Pneumonia Viral/complicações
19.
Drug Res (Stuttg) ; 70(9): 389-400, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32746481

RESUMO

The current outbreak of novel Coronavirus Disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major pandemic situation and a catastrophe for humans. COVID-19 is a severe infectious disease particularly of the respiratory system characterized by fatal complications such as severe acute respiratory distress syndrome (SARS), pneumonia, cardiac arrhythmia, kidney failure/ multiple organ failure and even death. Since its discovery, the SARS-CoV-2 has spread across 213 countries or territories, causing more than 8.5 million people with a rising death toll over 5.5 million people (as of June 2020, WHO). In fact, the current looming crisis of COVID-19 has become an increasingly serious concern to public health. It has affected lives of millions of people with severe impact on health systems and economies globally. Since there are no specific drugs and/or vaccines available so far, combating COVID-19 remains to be a major challenging task. Therefore, development of potential and effective treatment regimens (prophylactic/therapeutic) is urgently required which could resolve the issue. In this review, we summarize the current knowledge about the coronavirus, disease epidemiology, clinical manifestations and risk factors, replication of the virus, pathophysiology and host immune responses of SARS-CoV-2 infection. The therapeutic interventions and prophylactic measures along with precautionary measures are the frontline approaches that could be undertaken in order to control and prevent the spread of the deadly and highly contagious COVID-19 are also detailed herein.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Humanos , Imunoterapia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/transmissão , Vacinas Virais
20.
J Infect Dis ; 222(9): 1462-1467, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32798217

RESUMO

The scientific community has responded to the coronavirus disease 2019 (COVID-19) pandemic by rapidly undertaking research to find effective strategies to reduce the burden of this disease. Encouragingly, researchers from a diverse array of fields are collectively working towards this goal. Research with infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undertaken in high-containment laboratories; however, it is often desirable to work with samples at lower-containment levels. To facilitate the transfer of infectious samples from high-containment laboratories, we have tested methods commonly used to inactivate virus and prepare the sample for additional experiments. Incubation at 80°C, a range of detergents, Trizol reagents, and UV energies were successful at inactivating a high titer of SARS-CoV-2. Methanol and paraformaldehyde incubation of infected cells also inactivated the virus. These protocols can provide a framework for in-house inactivation of SARS-CoV-2 in other laboratories, ensuring the safe use of samples in lower-containment levels.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Inativação de Vírus , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/efeitos da radiação , Bioensaio , Pesquisa Biomédica , Chlorocebus aethiops , Detergentes , Formaldeído , Guanidinas , Temperatura Alta , Metanol , Fenóis , Polímeros , Raios Ultravioleta , Células Vero , Ensaio de Placa Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA