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1.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604797

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
2.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532085

RESUMO

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-ß1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antígenos Virais/imunologia , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Humanos , Interferons/metabolismo , Lipogênese/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Carga Viral/efeitos dos fármacos , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
3.
Emerg Microbes Infect ; 9(1): 1418-1428, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32529952

RESUMO

The Coronavirus disease 2019 (COVID-19), which is caused by the novel SARS-CoV-2 virus, is now causing a tremendous global health concern. Since its first appearance in December 2019, the outbreak has already caused over 5.8 million infections worldwide (till 29 May 2020), with more than 0.35 million deaths. Early virus-mediated immune suppression is believed to be one of the unique characteristics of SARS-CoV-2 infection and contributes at least partially to the viral pathogenesis. In this study, we identified the key viral interferon antagonists of SARS-CoV-2 and compared them with two well-characterized SARS-CoV interferon antagonists, PLpro and orf6. Here we demonstrated that the SARS-CoV-2 nsp13, nsp14, nsp15 and orf6, but not the unique orf8, could potently suppress primary interferon production and interferon signalling. Although SARS-CoV PLpro has been well-characterized for its potent interferon-antagonizing, deubiquitinase and protease activities, SARS-CoV-2 PLpro, despite sharing high amino acid sequence similarity with SARS-CoV, loses both interferon-antagonising and deubiquitinase activities. Among the 27 viral proteins, SARS-CoV-2 orf6 demonstrated the strongest suppression on both primary interferon production and interferon signalling. Orf6-deleted SARS-CoV-2 may be considered for the development of intranasal live-but-attenuated vaccine against COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Endorribonucleases/metabolismo , Exorribonucleases/metabolismo , Interferons/antagonistas & inibidores , Interferons/metabolismo , Metiltransferases/metabolismo , Pneumonia Viral/metabolismo , RNA Helicases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/metabolismo , Betacoronavirus/genética , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Endorribonucleases/genética , Exorribonucleases/genética , Interações Hospedeiro-Patógeno , Humanos , Interferons/genética , Metiltransferases/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/virologia , RNA Helicases/genética , Proteínas não Estruturais Virais/genética , Proteínas Virais/genética
4.
Autoimmun Rev ; 19(7): 102567, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376392

RESUMO

The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1ß, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1ß-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Citocinas/antagonistas & inibidores , Citocinas/uso terapêutico , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Interleucina-1beta , Interleucina-6 , Pandemias
5.
Cytokine Growth Factor Rev ; 53: 66-70, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32418715

RESUMO

The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Interferons/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Quimioterapia Combinada , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Oligonucleotídeos/uso terapêutico , Pandemias , Vacinas Virais/uso terapêutico
8.
Gene ; 751: 144761, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32407768

RESUMO

The ubiquitin specific peptidase (USP) family is involved in many life processes, of which antiviral is also an important basic function. One of the more important ways is to activate interferon. In this study, we reported the antiviral function of the ubiquitin specific peptidase 5(USP5) gene in zebrafish. Evolutionary and comparative protein sequence analysis of the USP5 was performed. The localization of USP5 in FHM cells cytoplasm was determined. Overexpression of USP5 significantly evoked higher expression of mRNA that encode IFNφ1 and ISGs, the promoteractivities of IFNφ1 and IFNstimulated response element (ISRE) were augmented likewise. USP5 was also able to enhance the expression of RIG-I and activate higher levels of IFNφ1 stimulated by Poly (I: C). Viral infection and interference tests demonstrated that USP5 inhibited the replication of SVCV in vitro. In summary, this study reveals that USP5 is able to activate higher levels of interferon by increasing RIG-I protein levels, and thus implement antivirus functions.


Assuntos
Proteases Específicas de Ubiquitina/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Sequência de Aminoácidos , Animais , Células Cultivadas , Interferons/biossíntese , Interferons/genética , Rhabdoviridae/fisiologia , Alinhamento de Sequência , Proteases Específicas de Ubiquitina/química , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , Replicação Viral , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Peixe-Zebra/virologia , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
9.
Dev Cell ; 53(5): 514-529.e3, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32425701

RESUMO

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.


Assuntos
Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/epidemiologia , Interferons/metabolismo , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Mucosa Respiratória/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Fumar Tabaco/genética , Adulto , Idoso , Animais , Células CACO-2 , Células Cultivadas , Feminino , Células HCT116 , Humanos , Interferons/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , Ratos , Transdução de Sinais , Análise de Célula Única , Fumar Tabaco/epidemiologia , Fumar Tabaco/metabolismo , Regulação para Cima
10.
Cell ; 181(5): 1036-1045.e9, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32416070

RESUMO

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus de RNA/imunologia , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Infecções por Coronavirus/genética , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/virologia , Interferons/genética , Interferons/imunologia , Pandemias , Pneumonia Viral/genética , Vírus de RNA/classificação , Transcrição Genética
11.
Cell Host Microbe ; 27(6): 883-890.e2, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32407669

RESUMO

The outbreaks of 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 infection have posed a severe threat to global public health. It is unclear how the human immune system responds to this infection. Here, we used metatranscriptomic sequencing to profile immune signatures in the bronchoalveolar lavage fluid of eight COVID-19 cases. The expression of proinflammatory genes, especially chemokines, was markedly elevated in COVID-19 cases compared to community-acquired pneumonia patients and healthy controls, suggesting that SARS-CoV-2 infection causes hypercytokinemia. Compared to SARS-CoV, which is thought to induce inadequate interferon (IFN) responses, SARS-CoV-2 robustly triggered expression of numerous IFN-stimulated genes (ISGs). These ISGs exhibit immunopathogenic potential, with overrepresentation of genes involved in inflammation. The transcriptome data was also used to estimate immune cell populations, revealing increases in activated dendritic cells and neutrophils. Collectively, these host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Pneumonia Viral/imunologia , Sistema Respiratório/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/análise , Interações Hospedeiro-Patógeno , Humanos , Interferons/metabolismo , Pandemias , Pneumonia Viral/patologia , Sistema Respiratório/patologia
12.
Cell Host Microbe ; 27(6): 870-878, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32464097

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Pneumonia Viral/imunologia , Animais , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Evasão da Resposta Imune , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais
14.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276399

RESUMO

When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses to in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.


Assuntos
Antivirais/farmacologia , Hepatite C/tratamento farmacológico , Hepatócitos/metabolismo , Imunidade Inata , Interferons/genética , Antivirais/uso terapêutico , Regulação da Expressão Gênica , Hepatite C/genética , Hepatite C/imunologia , Hepatócitos/imunologia , Humanos , Interferon Tipo I/genética
15.
Infect Dis Poverty ; 9(1): 45, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345362

RESUMO

BACKGROUND: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. METHODS: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test. RESULTS: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.


Assuntos
Betacoronavirus , Peptidil Dipeptidase A/genética , Receptores Virais/genética , Adulto , Fatores Etários , Idoso , Encéfalo/enzimologia , Sistema Cardiovascular/enzimologia , Sistema Cardiovascular/imunologia , Sistema Digestório/enzimologia , Sistema Digestório/imunologia , Glândulas Endócrinas/enzimologia , Glândulas Endócrinas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema Imunitário/enzimologia , Interferons/imunologia , Pulmão/enzimologia , Pulmão/imunologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Peptidil Dipeptidase A/sangue , RNA-Seq , Receptores Virais/sangue , Fatores Sexuais , Sistema Urogenital/enzimologia
16.
Brain Behav Immun ; 87: 59-73, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32334062

RESUMO

As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.


Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Corticosteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticoagulantes/uso terapêutico , Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Bevacizumab/uso terapêutico , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferons/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Células Matadoras Naturais , Medicina Tradicional Chinesa , Transplante de Células-Tronco Mesenquimais , Óxido Nítrico/uso terapêutico , Pandemias , Peptidil Dipeptidase A , Glicoproteína da Espícula de Coronavírus , Oligoelementos/uso terapêutico , Vacinas Virais/uso terapêutico , Vitaminas/uso terapêutico , Zinco/uso terapêutico
17.
Cell Host Microbe ; 27(5): 841-848.e3, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32289263

RESUMO

The ongoing pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underscores the urgency to develop experimental systems for studying this virus and identifying countermeasures. We report a reverse genetic system for SARS-CoV-2. Seven complimentary DNA (cDNA) fragments spanning the SARS-CoV-2 genome were assembled into a full-genome cDNA. RNA transcribed from the full-genome cDNA was highly infectious after electroporation into cells, producing 2.9 × 106 plaque-forming unit (PFU)/mL of virus. Compared with a clinical isolate, the infectious-clone-derived SARS-CoV-2 (icSARS-CoV-2) exhibited similar plaque morphology, viral RNA profile, and replication kinetics. Additionally, icSARS-CoV-2 retained engineered molecular markers and did not acquire other mutations. We generated a stable mNeonGreen SARS-CoV-2 (icSARS-CoV-2-mNG) by introducing this reporter gene into ORF7 of the viral genome. icSARS-CoV-2-mNG was successfully used to evaluate the antiviral activities of interferon (IFN). Collectively, the reverse genetic system and reporter virus provide key reagents to study SARS-CoV-2 and develop countermeasures.


Assuntos
Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , DNA Complementar/genética , Organismos Geneticamente Modificados/genética , Organismos Geneticamente Modificados/patogenicidade , Pneumonia Viral/virologia , Animais , Antivirais/uso terapêutico , Chlorocebus aethiops , Células Clonais , Infecções por Coronavirus/tratamento farmacológico , Genes Reporter/genética , Genoma Viral/genética , Interferons/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Viral/genética , Células Vero/virologia , Replicação Viral/fisiologia
18.
PLoS Pathog ; 16(3): e1008412, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226041

RESUMO

Bats are the natural reservoir host for a number of zoonotic viruses, including Hendra virus (HeV) which causes severe clinical disease in humans and other susceptible hosts. Our understanding of the ability of bats to avoid clinical disease following infection with viruses such as HeV has come predominantly from in vitro studies focusing on innate immunity. Information on the early host response to infection in vivo is lacking and there is no comparative data on responses in bats compared with animals that succumb to disease. In this study, we examined the sites of HeV replication and the immune response of infected Australian black flying foxes and ferrets at 12, 36 and 60 hours post exposure (hpe). Viral antigen was detected at 60 hpe in bats and was confined to the lungs whereas in ferrets there was evidence of widespread viral RNA and antigen by 60 hpe. The mRNA expression of IFNs revealed antagonism of type I and III IFNs and a significant increase in the chemokine, CXCL10, in bat lung and spleen following infection. In ferrets, there was an increase in the transcription of IFN in the spleen following infection. Liquid chromatography tandem mass spectrometry (LC-MS/MS) on lung tissue from bats and ferrets was performed at 0 and 60 hpe to obtain a global overview of viral and host protein expression. Gene Ontology (GO) enrichment analysis of immune pathways revealed that six pathways, including a number involved in cell mediated immunity were more likely to be upregulated in bat lung compared to ferrets. GO analysis also revealed enrichment of the type I IFN signaling pathway in bats and ferrets. This study contributes important comparative data on differences in the dissemination of HeV and the first to provide comparative data on the activation of immune pathways in bats and ferrets in vivo following infection.


Assuntos
Antígenos Virais/imunologia , Vírus Hendra/imunologia , Infecções por Henipavirus/imunologia , Imunidade Celular , Imunidade Inata , Pulmão/imunologia , Modelos Imunológicos , Animais , Antígenos Virais/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quirópteros , Furões , Vírus Hendra/genética , Infecções por Henipavirus/genética , Infecções por Henipavirus/patologia , Interferons/genética , Interferons/imunologia , Pulmão/patologia , Pulmão/virologia , Especificidade da Espécie
19.
Int J Antimicrob Agents ; 55(6): 105995, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32335281

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the previously unknown pathogen, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is now a global pandemic. There are no vaccines or specific treatments against this new virus; therefore, there is an urgent need to advance novel therapeutic interventions for COVID-19. Glycyrrhizin is a triterpene saponin with various biological functions and pharmacological effects. This brief article discusses the therapeutic potential of glycyrrhizin for the treatment of COVID-19 from the perspective of its pharmacological action, including binding angiotensin-converting enzyme II (ACE2), downregulating proinflammatory cytokines, inhibiting the accumulation of intracellular reactive oxygen species (ROS), inhibiting thrombin, inhibiting the hyperproduction of airway exudates, and inducing endogenous interferon.


Assuntos
Anti-Inflamatórios/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Ácido Glicirrízico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Citocinas/sangue , Humanos , Interferons/biossíntese , Interferons/imunologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
20.
EMBO Mol Med ; 12(6): e12465, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32333818

RESUMO

Coronavirus disease 2019 (COVID-19), triggered by the betacoronavirus SARS-CoV-2, has become one of the worst pandemics of our time that has already caused more than 250,000 deaths (JHU data-05/06/2020, https://coronavirus.jhu.edu/). Effective therapeutic approaches are urgently needed to reduce the spread of the virus and its death toll. Here, we assess the possibility of using interferon-lambda (IFNλ), a third type of interferon sharing low homology with type I IFNs and IL-10, for treating COVID-19 patients. We discuss the unique role of IFNλ in fine-tuning antiviral immunity in the respiratory tract to achieve optimal protection and minimal host damage and review early evidence that SARS-CoV-2 may impair IFNλ induction, leading to a delayed type I IFN-dominated response that triggers hyperinflammation and severe disease. We also consider the potential windows of opportunity for therapeutic intervention with IFNλ and potential safety considerations. We conclude that IFNλ constitutes a promising therapeutic agent for reducing viral presence and hyperinflammation in a single shot to prevent the devastating consequences of COVID-19 such as pneumonia and acute respiratory distress syndrome (ARDS).


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Interferons/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Inflamação/etiologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Carga Viral
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