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1.
BMC Bioinformatics ; 22(1): 18, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413085

RESUMO

BACKGROUND: The ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels. RESULTS: In this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection. CONCLUSIONS: H2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v .


Assuntos
/metabolismo , Infecções por Coronavirus/metabolismo , Bases de Dados Genéticas , Bases de Dados de Proteínas , Síndrome Respiratória Aguda Grave/metabolismo , Interface Usuário-Computador , /genética , /virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Proteômica , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia
2.
Nat Commun ; 12(1): 134, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420022

RESUMO

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.


Assuntos
/metabolismo , /transmissão , Ácidos Siálicos/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Ligação Viral , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Cricetinae , Furina/metabolismo , Células HEK293 , Heparitina Sulfato/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/virologia , Pulmão/patologia , Pulmão/virologia , Síndrome Respiratória Aguda Grave/patologia , Células Vero , Internalização do Vírus , Replicação Viral/fisiologia
3.
Front Immunol ; 11: 583373, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149733

RESUMO

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1ß and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1ß in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.


Assuntos
Caspase 1/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Inflamassomos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Betacoronavirus/imunologia , Coagulação Intravascular Disseminada/patologia , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Pandemias , Síndrome Respiratória Aguda Grave/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
4.
Int J Mol Sci ; 21(21)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138181

RESUMO

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.


Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Vasoconstrição/fisiologia , Betacoronavirus , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Sistema Calicreína-Cinina/fisiologia , Pandemias , Sistema Renina-Angiotensina/fisiologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos
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.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126657

RESUMO

Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin-angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1-9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin-angiotensin system and reducing the pathogen's cell entry could be a promising therapeutic strategy in the struggle against COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Proteína ADAM17/metabolismo , Animais , Betacoronavirus , Permeabilidade Capilar/fisiologia , Humanos , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Pandemias , Edema Pulmonar/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060566

RESUMO

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Lesão Pulmonar/genética , Pneumonia Viral/genética , Proteoma/genética , Proteômica/métodos , Síndrome Respiratória Aguda Grave/genética , Idoso , Autopsia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Redes e Vias Metabólicas , Anotação de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteoma/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais
8.
Front Immunol ; 11: 581338, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123167

RESUMO

Objectives: The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods: This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results: All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions: Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Unidades de Terapia Intensiva , Interleucina-10/sangue , Interleucina-6/sangue , Estudos Longitudinais , Linfopenia , Masculino , Pessoa de Meia-Idade , Pandemias , Projetos Piloto , Pneumonia Viral/imunologia , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
9.
Front Immunol ; 11: 587517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123171

RESUMO

Background and Objectives: Understanding the pathophysiology of respiratory failure in coronavirus disease 2019 (COVID-19) is indispensable for development of therapeutic strategies. Since we observed similarities between COVID-19 and interstitial lung disease in connective tissue disease (CTD-ILD), we investigated features of autoimmunity in SARS-CoV-2-associated respiratory failure. Methods: We prospectively enrolled 22 patients with RT-PCR-confirmed SARS-CoV-2 infection and 10 patients with non-COVID-19-associated pneumonia. Full laboratory testing was performed including autoantibody (AAB; ANA/ENA) screening using indirect immunofluorescence and immunoblot. Fifteen COVID-19 patients underwent high-resolution computed tomography. Transbronchial biopsies/autopsy tissue samples for histopathology and ultrastructural analyses were obtained from 4/3 cases, respectively. Results: Thirteen (59.1%) patients developed acute respiratory distress syndrome (ARDS), and five patients (22.7%) died from the disease. ANA titers ≥1:320 and/or positive ENA immunoblots were detected in 11/13 (84.6%) COVID-19 patients with ARDS, in 1/9 (11.1%) COVID-19 patients without ARDS (p = 0.002) and in 4/10 (40%) patients with non-COVID-19-associated pneumonias (p = 0.039). Detection of AABs was significantly associated with a need for intensive care treatment (83.3 vs. 10%; p = 0.002) and occurrence of severe complications (75 vs. 20%, p = 0.03). Radiological and histopathological findings were highly heterogeneous including patterns reminiscent of exacerbating CTD-ILD, while ultrastructural analyses revealed interstitial thickening, fibroblast activation, and deposition of collagen fibrils. Conclusions: We are the first to report overlapping clinical, serological, and imaging features between severe COVID-19 and acute exacerbation of CTD-ILD. Our findings indicate that autoimmune mechanisms determine both clinical course and long-term sequelae after SARS-CoV-2 infection, and the presence of autoantibodies might predict adverse clinical course in COVID-19 patients.


Assuntos
Doenças do Tecido Conjuntivo/patologia , Infecções por Coronavirus/patologia , Doenças Pulmonares Intersticiais/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Betacoronavirus/imunologia , Doenças do Tecido Conjuntivo/imunologia , Infecções por Coronavirus/imunologia , Feminino , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Estudos Prospectivos , Síndrome Respiratória Aguda Grave/imunologia
10.
Front Immunol ; 11: 580641, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101306

RESUMO

The ongoing outbreak of Coronavirus disease 2019 infection achieved pandemic status on March 11, 2020. As of September 8, 2020 it has caused over 890,000 mortalities world-wide. Coronaviral infections are enabled by potent immunoevasory mechanisms that target multiple aspects of innate immunity, with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) able to induce a cytokine storm, impair interferon responses, and suppress antigen presentation on both MHC class I and class II. Understanding the immune responses to SARS-CoV-2 and its immunoevasion approaches will improve our understanding of pathogenesis, virus clearance, and contribute toward vaccine and immunotherepeutic design and evaluation. This review discusses the known host innate immune response and immune evasion mechanisms driving SARS-CoV-2 infection and pathophysiology.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Humanos , Pandemias , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia
11.
Front Immunol ; 11: 584514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101314

RESUMO

Physical trauma can be considered an unrecognized "pandemic" because it can occur anywhere and affect anyone and represents a global burden. Following severe tissue trauma, patients frequently develop acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) despite modern surgical and intensive care concepts. The underlying complex pathophysiology of life-threatening ALI/ARDS has been intensively studied in experimental and clinical settings. However, currently, the coronavirus family has become the focus of ALI/ARDS research because it represents an emerging global public health threat. The clinical presentation of the infection is highly heterogeneous, varying from a lack of symptoms to multiple organ dysfunction and mortality. In a particular subset of patients, the primary infection progresses rapidly to ALI and ARDS. The pathophysiological mechanisms triggering and driving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ALI/ARDS are still poorly understood. Although it is also generally unknown whether insights from trauma-induced ARDS may be readily translated to SARS-CoV-2-associated ARDS, it was still recommended to treat coronavirus-positive patients with ALI/ARDS with standard protocols for ALI/ARDS. However, this strategy was questioned by clinical scientists, because it was documented that some severely hypoxic SARS-CoV-2-infected patients exhibited a normal respiratory system compliance, a phenomenon rarely observed in ARDS patients with another underlying etiology. Therefore, coronavirus-induced ARDS was defined as a specific ARDS phenotype, which accordingly requires an adjusted therapeutic approach. These suggestions reflect previous attempts of classifying ARDS into different phenotypes that might overall facilitate ARDS diagnosis and treatment. Based on the clinical data from ARDS patients, two major phenotypes have been proposed: hyper- and hypo-inflammatory. Here, we provide a comparative review of the pathophysiological pathway of trauma-/hemorrhagic shock-induced ARDS and coronavirus-induced ARDS, with an emphasis on the crucial key points in the pathogenesis of both these ARDS forms. Therefore, the manifold available data on trauma-/hemorrhagic shock-induced ARDS may help to better understand coronavirus-induced ARDS.


Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Trombose/patologia , Lesão Pulmonar Aguda/virologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Citocinas/sangue , Humanos , Imunidade Inata/imunologia , Inflamação/patologia , Inflamação/virologia , Pulmão/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Trombose/virologia
12.
Eur Rev Med Pharmacol Sci ; 24(16): 8592-8605, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32894567

RESUMO

OBJECTIVE: Lopinavir/ritonavir has been used for the treatment of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) coronavirus infections. It has been suggested that, based on this experience, this drug should also be studied in SARS-CoV2 infection. MATERIALS AND METHODS: We performed a systematic review of the literature regarding the use of lopinavir/ritonavir for the treatment of these three infections. We systematically searched the PubMed database from inception to April 30th, 2020, to identify in-vitro and animal studies and any reports of human use of lopinavir/ritonavir for the treatment of SARS, MERS and COVID-19. We also searched the Clinicatrial.gov to identify ongoing trials. RESULTS: Five in-vitro studies evaluated the effect of lopinavir/ritonavir in SARS. Three additional in-vitro studies reported the EC50 of the antiviral activity of lopinavir/ritonavir in MERS. We identified no in vitro studies evaluating the effect of lopinavir/ritonavir on the novel coronavirus. Two retrospective matched-cohort studies reported the use of lopinavir/ritonavir in combination with ribavirin for SARS patients. Three case reports and one retrospective study described the use of lopinavir/ritonavir in MERS. Twenty-two papers describe the use of lopinavir/ritonavir in adult patients with COVID-19. CONCLUSIONS: The existing literature does not suffice for assessing whether Lopinavir/ritonavir has any benefit in SARS, MERS or COVID-19.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Lopinavir/uso terapêutico , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Betacoronavirus/isolamento & purificação , Estudos Clínicos como Assunto , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Bases de Dados Factuais , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/patologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-32974224

RESUMO

SARS CoV appeared in 2003 in China, transmitted from bats to humans via eating infected animals. It affected 8,096 humans with a death rate of 11% affecting 21 countries. The receptor binding domain (RBD) in S protein of this virus gets attached with the ACE2 receptors present on human cells. MERS CoV was first reported in 2012 in Middle East, originated from bat and transmitted to humans through camels. MERS CoV has a fatality rate of 35% and last case reported was in 2017 making a total of 1,879 cases worldwide. DPP4 expressed on human cells is the main attaching site for RBD in S protein of MERS CoV. Folding of RBD plays a crucial role in its pathogenesis. Virus causing COVID-19 was named as SARS CoV-2 due its homology with SARS CoV that emerged in 2003. It has become a pandemic affecting nearly 200 countries in just 3 months' time with a death rate of 2-3% currently. The new virus is fast spreading, but it utilizes the same RBD and ACE2 receptors along with furin present in human cells. The lessons learned from the SARS and MERS epidemics are the best social weapons to face and fight against this novel global threat.


Assuntos
Infecções por Coronavirus/transmissão , Peptidil Dipeptidase A/genética , Pneumonia Viral/transmissão , Receptores Virais/genética , Síndrome Respiratória Aguda Grave/transmissão , Glicoproteína da Espícula de Coronavírus/genética , Animais , Betacoronavirus/genética , Betacoronavirus/metabolismo , Quirópteros/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Evolução Molecular , Furina/metabolismo , Genoma Viral/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Domínios Proteicos/genética , Receptores Virais/metabolismo , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/patologia , Glicoproteína da Espícula de Coronavírus/metabolismo
15.
Front Immunol ; 11: 2033, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922406

RESUMO

Immune dysfunction and aberrant cytokine storms often lead to rapid exacerbation of the disease during late infection stages in SARS-CoV and MERS-CoV patients. However, the underlying immunopathology mechanisms are not fully understood, and there has been little progress in research regarding the development of vaccines, anti-viral drugs, and immunotherapy. The newly discovered SARS-CoV-2 (2019-nCoV) is responsible for the third coronavirus pandemic in the human population, and this virus exhibits enhanced pathogenicity and transmissibility. SARS-CoV-2 is highly genetically homologous to SARS-CoV, and infection may result in a similar clinical disease (COVID-19). In this review, we provide detailed knowledge of the pathogenesis and immunological characteristics of SARS and MERS, and we present recent findings regarding the clinical features and potential immunopathogenesis of COVID-19. Host immunological characteristics of these three infections are summarised and compared. We aim to provide insights and scientific evidence regarding the pathogenesis of COVID-19 and therapeutic strategies targeting this disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Pneumonia Viral/patologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/patologia
16.
Infection ; 48(5): 665-669, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32737833

RESUMO

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


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Catepsinas/genética , Catepsinas/imunologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Ativação Enzimática/imunologia , Humanos , Evasão da Resposta Imune , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Ligação Proteica , Domínios Proteicos , Vírus da SARS/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/patologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus , Replicação Viral
17.
Tuberk Toraks ; 68(2): 160-167, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32755116

RESUMO

Novel coronavirus disease 2019 (COVID-19) which is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was first identified in December 2019 in Chinese town Wuhan and considered as a pandemic by World Health Organization. The disease has variety of symptoms including fever, shortness of breath, cough, fatigue, loss of smell and taste and diarrhea. While the majority of cases have mild symptoms, some progress to viral pneumonia, multi-organ failure, or cytokine storm and mortality is mostly caused by hypoxemic respiratory failure. Until now, more than 3.5 million people worldwide were infected and more than 240.000 mortality has been occurred. Thus, there is now evidence the disease may affect variety of organs according to accumulating biopsy and autopsy studies. Such pathological studies have potential role on the understanding of clinical outcomes and in the development of novel targeted therapeutic approaches. Given these aforementioned data, in the current manuscript we have summarized the pathological features of COVID-19 derived from biopsy and autopsy series.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Autopsia , Biópsia , Humanos , Pandemias
18.
Eur Rev Med Pharmacol Sci ; 24(14): 7816-7825, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744709

RESUMO

Currently, the outbreak and spread of coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are increasing worldwide. Furthermore, it has been considered as a major challenge, which threatens human beings and affects all aspects of their life. Understanding the cellular and molecular pathophysiology of the disease is currently under the focus of investigations. Accordingly, this turns the human scientific community attention to find a solution for addressing the challenge. The development of vaccines and efficient therapeutic modality is critical. So, both primary and clinical scientists are not only trying to decipher the structure of SARS-CoV-2, but also attempting to understand the underlying molecular mechanisms that cause tissues and cell injuries. SARS-CoV and SARS-CoV2 are highly homologous and share a highly similar function and behavior patterns. Therefore, this might guide us toward decoding the molecular mechanisms that are behind the SARS-CoV2 pathologic effects. It is noteworthy to mention that, the undesired host immune reactions play important roles in the pathophysiology of the disease, and it also seems that, renin-angiotensin signaling (RAS) is a key contributor in this regard. In this review, we provided a vision, highlight as well as discussing on potential therapeutic targets that might be considered to address the COVID-19 challenge.


Assuntos
Betacoronavirus/fisiologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Basigina/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Integrinas/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/virologia , Troponina I/metabolismo
19.
Pathog Dis ; 78(6)2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32840560

RESUMO

Coronavirus disease 2019 (COVID-19) is a viral pneumonia, responsible for the recent pandemic, and originated from Wuhan, China, in December 2019. The causative agent of the outbreak was identified as coronavirus and designated as severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). Few years back, the severe acute respiratory syndrome coronavirus (SARS- CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) were reported to be highly pathogenic and caused severe infections in humans. In the current situation SARS-CoV-2 has become the third highly pathogenic coronavirus that is responsible for the present outbreak in human population. At the time of this review, there were more than 14 007 791 confirmed COVID-19 patients which associated with over 597 105 deaths in more then 216 countries across the globe (as reported by World Health Organization). In this review we have discussed about SARS-CoV, MERS-CoV and SARC-CoV-2, their reservoirs, role of spike proteins and immunogenicity. We have also covered the diagnosis, therapeutics and vaccine status of SARS-CoV-2.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/patologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Reservatórios de Doenças/veterinária , Reservatórios de Doenças/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Zoonoses/virologia
20.
JCI Insight ; 5(19)2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32841215

RESUMO

The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.


Assuntos
Causas de Morte , Infecções por Coronavirus/patologia , Progressão da Doença , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Animais , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/fisiopatologia , Síndrome Respiratória Aguda Grave/fisiopatologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Replicação Viral/genética
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