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1.
Med Sci Monit ; 27: e930776, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34635632

RESUMO

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.


Assuntos
COVID-19/metabolismo , Hipóxia/virologia , Pneumonia Viral/virologia , Doenças Assintomáticas/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Hipóxia/epidemiologia , Hipóxia/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Pulmão/virologia , Microvasos/metabolismo , Oximetria , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Prevalência , SARS-CoV-2/isolamento & purificação , Trombose/metabolismo , Trombose/virologia
2.
Cell Rep ; 37(1): 109798, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587481

RESUMO

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Proteínas do Sistema Complemento/imunologia , Eosinófilos/imunologia , Inflamação/imunologia , Pneumonia Viral/imunologia , SARS-CoV-2/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo Antígeno-Anticorpo/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Eosinófilos/virologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Células Th2/imunologia , Carga Viral , Adulto Jovem
3.
Crit Care ; 25(1): 234, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217339

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) has induced a worldwide epidemiological event with a high infectivity and mortality. However, the predicting biomarkers and their potential mechanism in the progression of COVID-19 are not well known. OBJECTIVE: The aim of this study is to identify the candidate predictors of COVID-19 and investigate their underlying mechanism. METHODS: The retrospective study was conducted to identify the potential laboratory indicators with prognostic values of COVID-19 disease. Then, the prognostic nomogram was constructed to predict the overall survival of COVID-19 patients. Additionally, the scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of the most important prognostic indicators in lungs and peripherals, respectively. RESULTS: In total, 304 hospitalized adult COVID-19 patients in Wuhan Jinyintan Hospital were included in the retrospective study. CEA was the only laboratory indicator with significant difference in the univariate (P < 0.001) and multivariate analysis (P = 0.020). The scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of CEA in lungs and peripherals, respectively. The results revealed the potential roles of CEA were significantly distributed in type II pneumocytes of BALF and developing neutrophils of PBMCs, participating in the progression of COVID-19 by regulating the cell-cell communication. CONCLUSION: This study identifies the prognostic roles of CEA in COVID-19 patients and implies the potential roles of CEACAM8-CEACAM6 in the progression of COVID-19 by regulating the cell-cell communication of developing neutrophils and type II pneumocyte.


Assuntos
COVID-19/metabolismo , Antígeno Carcinoembrionário/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , COVID-19/mortalidade , Comunicação Celular , China/epidemiologia , Progressão da Doença , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Nomogramas , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Análise de Sobrevida
4.
Toxicol Appl Pharmacol ; 426: 115645, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271066

RESUMO

Elevated ambient temperatures and extreme weather events have increased the incidence of wildfires world-wide resulting in increased wood smoke particle (WSP). Epidemiologic data suggests that WSP exposure associates with exacerbations of respiratory diseases, and with increased respiratory viral infections. To assess the impact of WSP exposure on host response to viral pneumonia, we performed WSP exposures in rodents followed by infection with mouse adapted influenza (HINI-PR8). C57BL/6 male mice aged 6-8 weeks were challenged with WSP or PBS by oropharyngeal aspiration in acute (single dose) or sub-acute exposures (day 1, 3, 5, 7 and 10). Additional groups underwent sub-acute exposure followed by infection by influenza or heat-inactivated (HI) virus. Following exposures/infection, bronchoalveolar lavage (BAL) was performed to assess for total cell counts/differentials, total protein, protein carbonyls and hyaluronan. Lung tissue was assessed for viral counts by real time PCR. When compared to PBS, acute WSP exposure associated with an increase in airspace macrophages. Alternatively, sub-acute exposure resulted in a dose dependent increase in airspace neutrophils. Sub-acute WSP exposure followed by influenza infection was associated with improved respiratory viral outcomes including reduced weight loss and increased blood oxygen saturation, and decreased protein carbonyls and viral titers. Flow cytometry demonstrated dynamic changes in pulmonary macrophage and T cell subsets based on challenge with WSP and influenza. This data suggests that sub-acute WSP exposure can improve host response to acute influenza infection.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae , Pneumonia Viral , Fumaça , Incêndios Florestais , Administração por Inalação , Animais , Vírus da Influenza A Subtipo H1N1/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Transcriptoma , Replicação Viral , Madeira
5.
Infect Dis Now ; 51(5): 429-434, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34146758

RESUMO

INTRODUCTION: The SARS-CoV-2 virus affects many organs, especially the lungs, with widespread inflammation. We aimed to compare the endogenous oxidative damage markers of coenzyme Q10, nicotinamide dinucleotide oxidase 4, malondialdehyde, and ischemia-modified albumin levels in patients with pneumonia caused by SARS-CoV-2 and in an healthy control group. We also aimed to compare these parameters between patients with severe and non-severe pulmonary involvement. METHODS: The study included 58 adult patients with SARS-CoV-2 pneumonia and 30 healthy volunteers. CoQ10 and MDA levels were determined by high-pressure liquid chromatography. NOX4 and IMA levels were determined by ELISA assay and colorimetric method. RESULTS: Higher levels of CoQ10, MDA, NOX4, and IMA and lower levels of COQ10H were observed in patients with SARS-CoV-2 pneumonia than in the control group. MDA, IMA, NOX4, and CoQ10 levels were significantly higher in patients with severe pulmonary involvement than in patients with non-severe pulmonary involvement, but no significant difference was observed in CoQ10H levels. CoQ10 levels were significantly and positively correlated with both ferritin and CRP levels. CONCLUSION: SARS-CoV-2 pneumonia is significantly associated with increased endogenous oxidative damage. Oxidative damage seems to be associated with pulmonary involvement severity.


Assuntos
COVID-19/sangue , COVID-19/metabolismo , Estresse Oxidativo , Pneumonia Viral/sangue , Pneumonia Viral/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
6.
Am J Epidemiol ; 190(10): 2094-2106, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984860

RESUMO

Longitudinal trajectories of vital signs and biomarkers during hospital admission of patients with COVID-19 remain poorly characterized despite their potential to provide critical insights about disease progression. We studied 1884 patients with severe acute respiratory syndrome coronavirus 2 infection from April 3, 2020, to June 25, 2020, within 1 Maryland hospital system and used a retrospective longitudinal framework with linear mixed-effects models to investigate relevant biomarker trajectories leading up to 3 critical outcomes: mechanical ventilation, discharge, and death. Trajectories of 4 vital signs (respiratory rate, ratio of oxygen saturation (Spo2) to fraction of inspired oxygen (Fio2), pulse, and temperature) and 4 laboratory values (C-reactive protein (CRP), absolute lymphocyte count (ALC), estimated glomerular filtration rate, and D-dimer) clearly distinguished the trajectories of patients with COVID-19. Before any ventilation, log(CRP), log(ALC), respiratory rate, and Spo2-to-Fio2 ratio trajectories diverge approximately 8-10 days before discharge or death. After ventilation, log(CRP), log(ALC), respiratory rate, Spo2-to-Fio2 ratio, and estimated glomerular filtration rate trajectories again diverge 10-20 days before death or discharge. Trajectories improved until discharge and remained unchanged or worsened until death. Our approach characterizes the distribution of biomarker trajectories leading up to competing outcomes of discharge versus death. Moving forward, this model can contribute to quantifying the joint probability of biomarkers and outcomes when provided clinical data up to a given moment.


Assuntos
Biomarcadores/metabolismo , COVID-19/metabolismo , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/metabolismo , COVID-19/diagnóstico , COVID-19/epidemiologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Maryland/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Estudos Retrospectivos , SARS-CoV-2 , Sinais Vitais
7.
Immunity ; 54(6): 1186-1199.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915108

RESUMO

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Celular , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Receptor Notch4/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Anfirregulina/farmacologia , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imuno-Histoquímica , Imunomodulação/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Vírus da Influenza A/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pneumonia Viral/patologia , Receptor Notch4/antagonistas & inibidores , Receptor Notch4/genética , Índice de Gravidade de Doença
8.
Cells ; 10(5)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919158

RESUMO

Extracellular vesicles (EVs) refer to a heterogenous population of membrane-bound vesicles that are released by cells under physiological and pathological conditions. The detection of EVs in the majority of the bodily fluids, coupled with their diverse cargo comprising of DNA, RNA, lipids, and proteins, have led to the accumulated interests in leveraging these nanoparticles for diagnostic and therapeutic purposes. In particular, emerging studies have identified enhanced levels of a wide range of specific subclasses of non-coding RNAs (ncRNAs) in EVs, thereby suggesting the existence of highly selective and regulated molecular processes governing the sorting of these RNAs into EVs. Recent studies have also illustrated the functional relevance of these enriched ncRNAs in a variety of human diseases. This review summarizes the current state of knowledge on EV-ncRNAs, as well as their functions and significance in lung infection and injury. As a majority of the studies on EV-ncRNAs in lung diseases have focused on EV-microRNAs, we will particularly highlight the relevance of these molecules in the pathophysiology of these conditions, as well as their potential as novel biomarkers therein. We also outline the current challenges in the EV field amidst the tremendous efforts to propel the clinical utility of EVs for human diseases. The lack of published literature on the functional roles of other EV-ncRNA subtypes may in turn provide new avenues for future research to exploit their feasibility as novel diagnostic and therapeutic targets in human diseases.


Assuntos
Vesículas Extracelulares/fisiologia , Lesão Pulmonar/metabolismo , Pneumonia Bacteriana/metabolismo , Pneumonia Viral/metabolismo , RNA não Traduzido/fisiologia , Animais , Biomarcadores/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia
9.
Commun Biol ; 4(1): 172, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558616

RESUMO

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.


Assuntos
Interleucina-1/metabolismo , Pulmão/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Pneumonia Viral/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Células Cultivadas , Fumar Cigarros , Modelos Animais de Doenças , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Interleucina-1/genética , Pulmão/imunologia , Pulmão/virologia , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/virologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de Interleucina-1/genética , Transdução de Sinais
10.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33600379

RESUMO

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.


Assuntos
Envelhecimento/fisiologia , Vírus da Influenza A , Influenza Humana/patologia , Pulmão/patologia , Pneumonia Viral/patologia , SARS-CoV-2 , Linfócitos T Reguladores/patologia , Fatores Etários , Envelhecimento/metabolismo , Animais , COVID-19/complicações , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Humanos , Influenza Humana/complicações , Influenza Humana/metabolismo , Influenza Humana/virologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Linfócitos T Reguladores/metabolismo
11.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33140636

RESUMO

Cell entry, the fundamental step in cross-species transmission of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is initiated by the recognition of the host cell angiotensin-converting enzyme-2 (ACE2) receptor by the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. To date, several peptides have been proposed against SARS-CoV-2 both as inhibitor agents or as detection tools that can also be attached to the surfaces of nanoparticle carriers. But owing to their natural amino acid sequences, such peptides cannot be considered as efficient therapeutic candidates from a biostability point of view. This discussion demonstrates the design strategy of synthetic nonprotein amino acid substituted peptides with enhanced biostability and binding affinity, the implication of which can make those peptides potential therapeutic agents for inhibition and simple detection tools.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Sequência de Aminoácidos , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , COVID-19 , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Ligação Proteica/fisiologia , SARS-CoV-2 , Análise de Sequência de Proteína/métodos
12.
ACS Chem Neurosci ; 11(22): 3704-3706, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33147014

RESUMO

Postinfection complications of coronavirus disease 2019 (COVID-19) are still unknown, and one of the long-term concerns in infected people are brain pathologies. The question is that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be an environmental factor in accelerating the sporadic neurodegeneration in the infected population. In this regard, induction of protein aggregation in the brain by SARS-CoV-2 intact structure or a peptide derived from spike protein subunits needs to be considered in futures studies. In this paper, we discuss these possibilities using pieces of evidence from other viruses.


Assuntos
Betacoronavirus/metabolismo , Encéfalo/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Agregados Proteicos/fisiologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19 , Infecções por Coronavirus/patologia , Humanos , Pandemias , Pneumonia Viral/patologia , SARS-CoV-2 , Fatores de Tempo
13.
ACS Chem Neurosci ; 11(22): 3732-3740, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33147964

RESUMO

This Article summarizes the likely benefits of central nervous system oxidative preconditioning in the reduction of COVID-19 based on its putative pathogenesis. The current COVID-19 outbreak caused a pandemic with millions of infected patients and death cases worldwide. The clinical features of severe acute respiratory syndrome coronavirus (SARS-CoV) was initially linked with respiratory disorders, but recent studies have reported alterations of neurological and cerebrovascular functions in COVID-19 patients. The main viral infection features are related to cell death, inflammation, and cytokine generation, which can be associated with the dysregulation of redox systems or oxidative stress. However, until now, there is no available and effective therapeutic approach. Thus, it is necessary to search for care and adequate protection against the disease, especially for susceptible and vulnerable groups. Preconditioning, a well-known antioxidative stress and anti-inflammatory approach, is protective against many neurological age-related disorders. COVID-19 severity and morbidity have been observed in elderly patients. The aim of the present study is to elucidate the possible protective role of oxidative preconditioning in aged patients at high risk of developing severe COVID-19 complications.


Assuntos
Betacoronavirus , Encéfalo/irrigação sanguínea , Infecções por Coronavirus/terapia , Precondicionamento Isquêmico/métodos , Estresse Oxidativo/fisiologia , Pneumonia Viral/terapia , Betacoronavirus/metabolismo , Encéfalo/metabolismo , Encéfalo/virologia , COVID-19 , Infecções por Coronavirus/metabolismo , Humanos , Precondicionamento Isquêmico/tendências , Pandemias , Pneumonia Viral/metabolismo , SARS-CoV-2
14.
Int J Mol Sci ; 21(21)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158276

RESUMO

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus-host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein-protein interfaces responsible for virus entry and infection transmission.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2 , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Receptores Virais/metabolismo , SARS-CoV-2 , Transdução de Sinais , Internalização do Vírus
15.
Sci Rep ; 10(1): 19395, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173052

RESUMO

An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.


Assuntos
Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Perfilação da Expressão Gênica , Pulmão/metabolismo , Terapia de Alvo Molecular , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Surfactantes Pulmonares/metabolismo , Biologia de Sistemas , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Epigênese Genética , Humanos , Pulmão/efeitos dos fármacos , Especificidade de Órgãos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Virais/metabolismo
17.
Sci Immunol ; 5(53)2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158975

RESUMO

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-ß present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Memória Imunológica/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , SARS-CoV-2/imunologia , Fatores Etários , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/imunologia , Influenza Humana/metabolismo , Influenza Humana/virologia , Pulmão/metabolismo , Pulmão/virologia , Camundongos Endogâmicos C57BL , Orthomyxoviridae/imunologia , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2/fisiologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
18.
Nat Commun ; 11(1): 5838, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203860

RESUMO

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais , Animais , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Cricetinae , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Pulmão/patologia , Pulmão/virologia , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , SARS-CoV-2 , Fator de Transcrição STAT2/genética , Replicação Viral
20.
Comput Biol Med ; 126: 104051, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33131530

RESUMO

SARS-CoV-2 has ushered a global pandemic with no effective drug being available at present. Although several FDA-approved drugs are currently under clinical trials for drug repositioning, there is an on-going global effort for new drug identification. In this paper, using multi-omics (interactome, proteome, transcriptome, and bibliome) data and subsequent integrated analysis, we present the biological events associated with SARS-CoV-2 infection and identify several candidate drugs against this viral disease. We found that: (i) Interactome-based infection pathways differ from the other three omics-based profiles. (ii) Viral process, mRNA splicing, cytokine and interferon signaling, and ubiquitin mediated proteolysis are important pathways in SARS-CoV-2 infection. (iii) SARS-CoV-2 infection also shares pathways with Influenza A, Epstein-Barr virus, HTLV-I, Measles, and Hepatitis virus. (iv) Further, bacterial, parasitic, and protozoan infection pathways such as Tuberculosis, Malaria, and Leishmaniasis are also shared by this virus. (v) A total of 50 candidate drugs, including the prophylaxis agents and pathway specific inhibitors are identified against COVID-19. (vi) Betamethasone, Estrogen, Simvastatin, Hydrocortisone, Tositumomab, Cyclosporin A etc. are among the important drugs. (vii) Ozone, Nitric oxide, plasma components, and photosensitizer drugs are also identified as possible therapeutic candidates. (viii) Curcumin, Retinoic acids, Vitamin D, Arsenic, Copper, and Zinc may be the candidate prophylaxis agents. Nearly 70% of our identified agents are previously suggested to have anti-COVID-19 effects or under clinical trials. Among our identified drugs, the ones that are not yet tested, need validation with caution while an appropriate drug combination from these candidate drugs along with a SARS-CoV-2 specific antiviral agent is needed for effective COVID-19 management.


Assuntos
Antivirais , Betacoronavirus , Infecções por Coronavirus , Bases de Dados Genéticas , Descoberta de Drogas , Modelos Biológicos , Pandemias , Pneumonia Viral , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/metabolismo , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Proteômica , SARS-CoV-2
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