RESUMO
In December 2019, rising pneumonia cases caused by a novel ß-coronavirus (SARS-CoV-2) occurred in Wuhan, China, which has rapidly spread worldwide, causing thousands of deaths. The WHO declared the SARS-CoV-2 outbreak as a public health emergency of international concern, since then several scientists are dedicated to its study. It has been observed that many human viruses have codon usage biases that match highly expressed proteins in the tissues they infect and depend on the host cell machinery for the replication and co-evolution. In this work, we analysed 91 molecular features and codon usage patterns for 339 viral genes and 463 human genes that consisted of 677,873 codon positions. Hereby, we selected the highly expressed genes from human lung tissue to perform computational studies that permit to compare their molecular features with those of SARS, SARS-CoV-2 and MERS genes. The integrated analysis of all the features revealed that certain viral genes and overexpressed human genes have similar codon usage patterns. The main pattern was the A/T bias that together with other features could propitiate the viral infection, enhanced by a host dependant specialization of the translation machinery of only some of the overexpressed genes. The envelope protein E, the membrane glycoprotein M and ORF7 could be further benefited. This could be the key for a facilitated translation and viral replication conducting to different comorbidities depending on the genetic variability of population due to the host translation machinery. This is the first codon usage approach that reveals which human genes could be potentially deregulated due to the codon usage similarities between the host and the viral genes when the virus is already inside the human cells of the lung tissues. Our work leaded to the identification of additional highly expressed human genes which are not the usual suspects but might play a role in the viral infection and settle the basis for further research in the field of human genetics associated with new viral infections. To identify the genes that could be deregulated under a viral infection is important to predict the collateral effects and determine which individuals would be more susceptible based on their genetic features and comorbidities associated.
Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Códon/genética , Uso do Códon , Biologia Computacional/métodos , Coronavirus/genética , Infecções por Coronavirus/metabolismo , Genes Virais , Genoma Viral , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Filogenia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , SARS-CoV-2/genéticaRESUMO
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has produced significant health emergencies worldwide, resulting in the declaration by the World Health Organization of the coronavirus disease 2019 (COVID-19) pandemic. Acute respiratory syndrome seems to be the most common manifestation of COVID-19. A high proportion of patients require intensive care unit admission and mechanical ventilation (MV) to survive. It has been well established that angiotensin-converting enzyme type 2 (ACE2) is the primary cellular receptor for SARS-CoV-2. ACE2 belongs to the renin-angiotensin system (RAS), composed of several peptides, such as angiotensin II (Ang II) and angiotensin (1-7) (Ang-(1-7)). Both peptides regulate muscle mass and function. It has been described that SARS-CoV-2 infection, by direct and indirect mechanisms, affects a broad range of organ systems. In the skeletal muscle, through unbalanced RAS activity, SARS-CoV-2 could induce severe consequences such as loss of muscle mass, strength, and physical function, which will delay and interfere with the recovery process of patients with COVID-19. This article discusses the relationship between RAS, SARS-CoV-2, skeletal muscle, and the potentially harmful consequences for skeletal muscle in patients currently infected with and recovering from COVID-19.
Assuntos
Infecções por Coronavirus/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina , Animais , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Humanos , Músculo Esquelético/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologiaRESUMO
The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.
Assuntos
Infecções por Coronavirus/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Pneumonia Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , COVID-19 , Infecções por Coronavirus/patologia , Feminino , Humanos , Interleucina-13/genética , Interleucina-4/genética , Pulmão/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Esfingosina/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: We aimed to present a review of renal changes in patients with COVID-19. METHODS: We performed a systematic review of the literature to identify original articles regarding clinical, laboratory, and anatomopathological kidney changes in patients infected with SARS-CoV-2 published until May 7, 2020. The search was carried out across PubMed, Scopus, and Embase using the keywords "COVID-19", "coronavirus", "SARS-CoV-2", "kidney injury" and "kidney disease". Fifteen studies presented clinical and laboratory renal changes in patients with COVID-19, and three addressed anatomopathological changes. DISCUSSION: Acute kidney injury (AKI) was a relevant finding in patients with COVID-19. There were also significant changes in laboratory tests that indicated kidney injury, such as increased serum creatinine and blood urea nitrogen (BUN), proteinuria, and hematuria. The presence of laboratory abnormalities and AKI were significant in severely ill patients. There was a considerable prevalence of AKI among groups of patients who died of COVID-19. Histopathological analysis of the kidney tissue of patients infected with SARS-CoV-2 suggested that the virus may directly affect the kidneys. CONCLUSION: Although COVID-19 affects mainly the lungs, it can also impact the kidneys. Increased serum creatinine and BUN, hematuria, proteinuria, and AKI were frequent findings in patients with severe COVID-19 and were related to an increased mortality rate. Further studies focusing on renal changes and their implications for the clinical condition of patients infected with the novel coronavirus are needed.
Assuntos
Injúria Renal Aguda/etiologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Injúria Renal Aguda/fisiopatologia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/urina , Creatinina/sangue , Hematúria/etiologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/urina , Proteinúria/etiologia , SARS-CoV-2 , Urina/químicaRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.
Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Fatores Etários , Enzima de Conversão de Angiotensina 2 , Animais , Antígenos de Neoplasias/metabolismo , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Suscetibilidade a Doenças , Estrogênios/metabolismo , Feminino , Humanos , Pulmão/patologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Receptores de Estrogênio/metabolismo , SARS-CoV-2 , Fatores Sexuais , Transdução de SinaisRESUMO
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the corona virus disease-19 which is accompanied by severe pneumonia, pulmonary alveolar collapses and which stops oxygen exchange. Viral transmissibility and pathogenesis depend on recognition by a receptor in the host, protease cleavage of the host membrane and fusion. SARS-CoV-2 binds to the angiotensin converting enzyme 2 receptor. Here, we discuss the general characteristics of the virus, its mechanism of action and the way in which the mechanism correlates with the comorbidities that increase the death rate. We also discuss the currently proposed therapeutic measures and propose the use of antioxidant drugs to help patients infected with the SARS-CoV-2. Oxidizing agents come from phagocytic leukocytes such as neutrophils, monocytes, macrophages and eosinophils that invade tissue. Free radicals promote cytotoxicity thus injuring cells. They also trigger the mechanism of inflammation by mediating the activation of NFkB and inducing the transcription of cytokine production genes. Release of cytokines enhances the inflammatory response. Oxidative stress is elevated during critical illnesses and contributes to organ failure. In corona virus disease-19 there is an intense inflammatory response known as a cytokine storm that could be mediated by oxidative stress. Although antioxidant therapy has not been tested in corona virus disease-19, the consequences of antioxidant therapy in sepsis, acute respiratory distress syndrome and acute lung injury are known. It improves oxygenation rates, glutathione levels and strengthens the immune response. It reduces mechanical ventilation time, the length of stay in the intensive care unit, multiple organ dysfunctions and the length of stay in the hospital and mortality rates in acute lung injury/acute respiratory distress syndrome and could thus help patients with corona virus disease-19.
Assuntos
Antioxidantes/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Indústria Alimentícia/legislação & jurisprudência , Política de Saúde/legislação & jurisprudência , Obesidade/epidemiologia , Pneumonia Viral/epidemiologia , Comportamento de Redução do Risco , COVID-19 , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Humanos , México/epidemiologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/metabolismo , Pneumonia Viral/prevenção & controle , SARS-CoV-2RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.
Assuntos
Antivirais/farmacologia , Sulfato de Atazanavir/farmacologia , Betacoronavirus/efeitos dos fármacos , Citocinas/metabolismo , Ritonavir/farmacologia , Animais , Sulfato de Atazanavir/química , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , COVID-19 , Morte Celular/efeitos dos fármacos , Chlorocebus aethiops , Proteases 3C de Coronavírus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Quimioterapia Combinada , Humanos , Inflamação/metabolismo , Inflamação/virologia , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Monócitos/virologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Inibidores de Proteases/farmacologia , SARS-CoV-2 , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/ß3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.
Assuntos
Betacoronavirus/imunologia , Transtornos da Coagulação Sanguínea/patologia , Plaquetas/patologia , Infecções por Coronavirus/complicações , Monócitos/patologia , Pneumonia Viral/complicações , Tromboplastina/metabolismo , Adulto , Biomarcadores/metabolismo , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/metabolismo , Transtornos da Coagulação Sanguínea/virologia , Plaquetas/metabolismo , Plaquetas/virologia , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/virologia , Selectina-P/metabolismo , Pandemias , Ativação Plaquetária , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Prognóstico , Estudos Prospectivos , SARS-CoV-2 , Taxa de SobrevidaRESUMO
The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.