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1.
Nat Commun ; 12(1): 4117, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226537

RESUMO

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Síndrome da Liberação de Citocina/complicações , Monócitos/patologia , Ativação de Neutrófilo , Idoso , Células Apresentadoras de Antígenos/imunologia , COVID-19/sangue , COVID-19/virologia , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Citocinas/sangue , Armadilhas Extracelulares/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
2.
Nat Commun ; 12(1): 4195, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234119

RESUMO

SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Animais , Sítios de Ligação , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Cães , Células HeLa , Humanos , Mutação , Ligação Proteica , Domínios Proteicos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
3.
Nat Cell Biol ; 23(7): 718-732, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34239064

RESUMO

Patients with Coronavirus disease 2019 exhibit low expression of interferon-stimulated genes, contributing to a limited antiviral response. Uncovering the underlying mechanism of innate immune suppression and rescuing the innate antiviral response remain urgent issues in the current pandemic. Here we identified that the dimerization domain of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is required for SARS2-NP to undergo liquid-liquid phase separation with RNA, which inhibits Lys63-linked poly-ubiquitination and aggregation of MAVS and thereby suppresses the innate antiviral immune response. Mice infected with an RNA virus carrying SARS2-NP exhibited reduced innate immunity, an increased viral load and high morbidity. Notably, we identified SARS2-NP acetylation at Lys375 by host acetyltransferase and reported frequently occurring acetylation-mimicking mutations of Lys375, all of which impaired SARS2-NP liquid-liquid phase separation with RNA. Importantly, a peptide targeting the dimerization domain was screened out to disrupt the SARS2-NP liquid-liquid phase separation and demonstrated to inhibit SARS-CoV-2 replication and rescue innate antiviral immunity both in vitro and in vivo.


Assuntos
Proteínas do Nucleocapsídeo/imunologia , Proteínas do Nucleocapsídeo/metabolismo , SARS-CoV-2/genética , Animais , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Camundongos , Proteínas do Nucleocapsídeo/genética , Vírus de RNA/genética , SARS-CoV-2/fisiologia
4.
Science ; 373(6551): 231-236, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244417

RESUMO

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.


Assuntos
RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Interferência de RNA , Vírus de RNA/fisiologia , RNA Viral/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismo , Células-Tronco/enzimologia , Células-Tronco/virologia , Processamento Alternativo , Animais , Encéfalo/enzimologia , Encéfalo/virologia , Linhagem Celular , RNA Helicases DEAD-box/química , Humanos , Imunidade Inata , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Organoides/enzimologia , Organoides/virologia , Infecções por Vírus de RNA/enzimologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Vírus de RNA/imunologia , RNA de Cadeia Dupla/metabolismo , RNA Interferente Pequeno/metabolismo , Ribonuclease III/química , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Replicação Viral , Zika virus/genética , Zika virus/imunologia , Zika virus/fisiologia , Infecção por Zika virus/enzimologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
5.
Eur J Med Res ; 26(1): 75, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256840

RESUMO

BACKGROUND: The aim of this study was to evaluate the expression of four up/down-regulated inflammatory miRNAs and their mRNA targets in the serum samples of COVID-19 patients with different grades. Also, we investigated the relative expression of these miRNAs and mRNAs during hospitalization. METHODS: In this cross-sectional study, 5 mL of blood sample were taken from COVID-19 patients with different grades and during hospitalization from several health centers of Yazd, Tehran, and Zahedan province of Iran from December 20, 2020 to March 2, 2021. The relative expression of miRNAs and mRNAs was evaluated by q-PCR. RESULTS: We found that the relative expression of hsa-miR-31-3p, hsa-miR-29a-3p, and hsa-miR-126-3p was significantly decreased and the relative expression of their mRNA targets (ZMYM5, COL5A3, and CAMSAP1) was significantly increased with the increase of disease grade. Conversely, the relative expression of hsa-miR-17-3p was significantly increased and its mRNA target (DICER1) was significantly decreased with the increase of disease grade. This pattern was exactly seen during hospitalization of COVID-19 patients who did not respond to treatment. In COVID-19 patients who responded to treatment, the expression of selected miRNAs and their mRNA targets returned to the normal level. A negative significant correlation was seen between (1) the expression of hsa-miR-31-3p and ZMYM5, (2) hsa-miR-29a-3p and COL5A3, (3) hsa-miR-126-3p and CAMSAP1, and (4) hsa-miR-17-3p and DICER1 in COVID-19 patients with any grade (P < 0.05) and during hospitalization. CONCLUSIONS: In this study, we gained a more accurate understanding of the expression of up/down-regulated inflammatory miRNAs in the blood of COVID-19 patients. The obtained data may help us in the diagnosis and prognosis of COVID-19. TRIAL REGISTRATION: The ethics committee of Zahedan University of Medical Sciences, Zahedan, Iran. (Ethical Code: IR.ZAUMS.REC.1399.316) was registered for this project.


Assuntos
COVID-19/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , RNA Mensageiro/genética , COVID-19/sangue , COVID-19/virologia , Proteínas de Transporte/genética , Colágeno/genética , Estudos Transversais , RNA Helicases DEAD-box/genética , Hospitalização/estatística & dados numéricos , Humanos , Irã (Geográfico) , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , Ribonuclease III/genética , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
6.
Hist Philos Life Sci ; 43(3): 91, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34258692

RESUMO

Ageism has unfortunately become a salient phenomenon during the COVID-19 pandemic. In particular, triage decisions based on age have been hotly discussed. In this article, I first defend that, although there are ethical reasons (founded on the principles of benefit and fairness) to consider the age of patients in triage dilemmas, using age as a categorical exclusion is an unjustifiable ageist practice. Then, I argue that ageism during the pandemic has been fueled by media narratives and unfair assumptions which have led to an ethically problematic group homogenization of the older population. Finally, I conclude that an intersectional perspective can shed light on further controversies on ageism and triage in the post-pandemic future.


Assuntos
Ageismo/ética , COVID-19/terapia , Triagem/ética , Ageismo/prevenção & controle , Ageismo/psicologia , Ageismo/estatística & dados numéricos , Humanos , SARS-CoV-2/fisiologia , Triagem/estatística & dados numéricos
7.
BMC Infect Dis ; 21(1): 688, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271860

RESUMO

BACKGROUND: Being able to use COVID-19 RT-PCR Ct values as simple clinical markers of disease outcome or prognosis would allow for the easy and proactive identification and triaging of high-risk cases. This study's objective was thus to explore whether a correlation exists between COVID-19 viral loads, as indicated by RT-PCR Ct values, and disease severity, as indicated by respiratory indices. RESULTS: A multi-centre cross-sectional retrospective study was conducted, using data obtained from Bahrain's National COVID-19 Task force's centralised database. The study period ranged from May 2, 2020 to July 31, 2020. A multivariable logistic regression was used to assess for a correlation using data from a total of 1057 admitted COVID-19 cases. The covariates adjusted for included sex, age, presentation, and comorbidities. In our cohort, Ct value showed no statistical significance for an association with requirement for oxygenation on admission (Odds ratio 1.046; 95%CI 0.999 to 1.096, p = 0.054). CONCLUSION: Viral load, as indicated by Ct values, did not seem to be associated with requirement for oxygenation on admission in our cohort. We postulate however that time since onset of symptom may have acted as an unaccounted-for confounder. As such, RT-PCR Ct values may not be a useful prognostic clinical tool in isolation.


Assuntos
COVID-19/diagnóstico , COVID-19/patologia , SARS-CoV-2/fisiologia , Carga Viral/fisiologia , Adulto , Idoso , Barein/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Coortes , Comorbidade , Estudos Transversais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Testes Sorológicos , Índice de Gravidade de Doença , Carga Viral/estatística & dados numéricos
8.
BMC Infect Dis ; 21(1): 687, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271868

RESUMO

BACKGROUND: COVID-19 can occur asymptomatically, as influenza-like illness, or as more severe forms, which characterize severe acute respiratory syndrome (SARS). Its mortality rate is higher in individuals over 80 years of age and in people with comorbidities, so these constitute the risk group for severe forms of the disease. We analyzed the factors associated with death in confirmed cases of COVID-19 in the state of Rio de Janeiro. This cross-sectional study evaluated the association between individual demographic, clinical, and epidemiological variables and the outcome (death) using data from the Unified Health System information systems. METHODS: We used the extreme boosting gradient (XGBoost) model to analyze the data, which uses decision trees weighted by the estimation difficulty. To evaluate the relevance of each independent variable, we used the SHapley Additive exPlanations (SHAP) metric. From the probabilities generated by the XGBoost model, we transformed the data to the logarithm of odds to estimate the odds ratio for each independent variable. RESULTS: This study showed that older individuals of black race/skin color with heart disease or diabetes who had dyspnea or fever were more likely to die. CONCLUSIONS: The early identification of patients who may progress to a more severe form of the disease can help improve the clinical management of patients with COVID-19 and is thus essential to reduce the lethality of the disease.


Assuntos
COVID-19/epidemiologia , COVID-19/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/patologia , Criança , Pré-Escolar , Cidades/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Medição de Risco , Fatores de Risco , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Fatores Socioeconômicos , Análise de Sobrevida , Adulto Jovem
9.
BMC Infect Dis ; 21(1): 686, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271870

RESUMO

BACKGROUND: Associations between community-level risk factors and COVID-19 incidence have been used to identify vulnerable subpopulations and target interventions, but the variability of these associations over time remains largely unknown. We evaluated variability in the associations between community-level predictors and COVID-19 case incidence in 351 cities and towns in Massachusetts from March to October 2020. METHODS: Using publicly available sociodemographic, occupational, environmental, and mobility datasets, we developed mixed-effect, adjusted Poisson regression models to depict associations between these variables and town-level COVID-19 case incidence data across five distinct time periods from March to October 2020. We examined town-level demographic variables, including population proportions by race, ethnicity, and age, as well as factors related to occupation, housing density, economic vulnerability, air pollution (PM2.5), and institutional facilities. We calculated incidence rate ratios (IRR) associated with these predictors and compared these values across the multiple time periods to assess variability in the observed associations over time. RESULTS: Associations between key predictor variables and town-level incidence varied across the five time periods. We observed reductions over time in the association with percentage of Black residents (IRR = 1.12 [95%CI: 1.12-1.13]) in early spring, IRR = 1.01 [95%CI: 1.00-1.01] in early fall) and COVID-19 incidence. The association with number of long-term care facility beds per capita also decreased over time (IRR = 1.28 [95%CI: 1.26-1.31] in spring, IRR = 1.07 [95%CI: 1.05-1.09] in fall). Controlling for other factors, towns with higher percentages of essential workers experienced elevated incidences of COVID-19 throughout the pandemic (e.g., IRR = 1.30 [95%CI: 1.27-1.33] in spring, IRR = 1.20 [95%CI: 1.17-1.22] in fall). Towns with higher proportions of Latinx residents also had sustained elevated incidence over time (IRR = 1.19 [95%CI: 1.18-1.21] in spring, IRR = 1.14 [95%CI: 1.13-1.15] in fall). CONCLUSIONS: Town-level COVID-19 risk factors varied with time in this study. In Massachusetts, racial (but not ethnic) disparities in COVID-19 incidence may have decreased across the first 8 months of the pandemic, perhaps indicating greater success in risk mitigation in selected communities. Our approach can be used to evaluate effectiveness of public health interventions and target specific mitigation efforts on the community level.


Assuntos
COVID-19/epidemiologia , Ocupações/estatística & dados numéricos , Meio Social , Transportes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/etnologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Disparidades nos Níveis de Saúde , Humanos , Incidência , Renda/estatística & dados numéricos , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Movimento/fisiologia , Pandemias , Características de Residência/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2/fisiologia , Fatores Socioeconômicos , Fatores de Tempo , Populações Vulneráveis/etnologia , Populações Vulneráveis/estatística & dados numéricos , Adulto Jovem
10.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196300

RESUMO

BACKGROUNDSARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODSWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR-based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTSThis study included 300 participants with nucleic acid test-confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4-25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5-10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSIONThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDINGMark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).


Assuntos
COVID-19/sangue , COVID-19/virologia , SARS-CoV-2 , Viremia/sangue , Viremia/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Pandemias , Prognóstico , Proteoma/metabolismo , Proteômica , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Internalização do Vírus
11.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201797

RESUMO

The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Dexametasona/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Inflamação/tratamento farmacológico , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Replicação Viral/efeitos dos fármacos
12.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202844

RESUMO

The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group. Various antiviral mechanisms shown by crude plant extracts and plant-derived bioactive compounds are discussed. The understanding of the action mechanisms of complex plant extract and isolated plant-derived compounds will help pave the way towards the combat of this life-threatening disease. Further, molecular docking studies, in silico analyses of extracted compounds, and future prospects are included. The in vitro production of antiviral chemical compounds from plants using molecular pharming is also considered. Notably, hairy root cultures represent a promising and sustainable way to obtain a range of biologically active compounds that may be applied in the development of novel antiviral agents.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Extratos Vegetais/farmacologia , Plantas Medicinais/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/imunologia , Antivirais/uso terapêutico , Simulação por Computador , Humanos , Agricultura Molecular/métodos , Extratos Vegetais/química , Extratos Vegetais/imunologia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/imunologia , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
13.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34226277

RESUMO

Here, we recorded serum proteome profiles of 33 severe COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later time points. With the aim to predict treatment outcome, we focused on serum proteins different in abundance between the group of survivors and non-survivors. We observed that a small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, histidine-rich glycoprotein, and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3, and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also showed opposite trends in protein abundance during disease progression. We defined an optimal panel of nine proteins for mortality risk assessment. The prediction power of this mortality risk panel was evaluated against two recent COVID-19 serum proteomics studies on independent cohorts measured in other laboratories in different countries and observed to perform very well in predicting mortality also in these cohorts. This panel may not be unique for COVID-19 as some of the proteins in the panel have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Proteoma/metabolismo , Índice de Gravidade de Doença , Idoso , COVID-19/virologia , Estudos de Coortes , Feminino , Hospitalização , Humanos , Imunoglobulinas/sangue , Masculino , SARS-CoV-2/fisiologia , Sobreviventes
14.
J Chem Phys ; 154(19): 195104, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34240889

RESUMO

Biological processes at the cellular level are stochastic in nature, and the immune response system is no different. Therefore, models that attempt to explain this system need to also incorporate noise or fluctuations that can account for the observed variability. In this work, a stochastic model of the immune response system is presented in terms of the dynamics of T cells and virus particles. Making use of the Green's function and the Wilemski-Fixman approximation, this model is then solved to obtain the analytical expression for the joint probability density function of these variables in the early and late stages of infection. This is then also used to calculate the average level of virus particles in the system. Upon comparing the theoretically predicted average virus levels to those of COVID-19 patients, it is hypothesized that the long-lived dynamics that are characteristics of such viral infections are due to the long range correlations in the temporal fluctuations of the virions. This model, therefore, provides an insight into the effects of noise on viral dynamics.


Assuntos
Imunidade , Modelos Imunológicos , Linfócitos T/imunologia , Linfócitos T/virologia , Vírion/fisiologia , SARS-CoV-2/fisiologia , Processos Estocásticos
15.
Am J Chin Med ; 49(5): 1045-1061, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225580

RESUMO

A novel coronavirus named SARS-CoV-2 is causing the severe acute pneumonia (COVID-19) and rapid spread nationally and internationally, resulting in a major global health emergency. Chinese governments and scientists have implemented a series of rigorous measures and scientific research to prevent and control the SARS-CoV-2 infection. However, there is still no specific antiviral drug or vaccine against SARS-CoV-2. It has been proven that traditional Chinese medicine (TCM) exerts an important role in the prevention and treatment of the COVID-19 caused by SARS-CoV-2 during the outbreak. Although the therapeutic effects of these TCM formulas are attractive, the molecular mechanism of action has not been fully elucidated. An emerging strategy of systems pharmacology has been proposed to be a promising method to interpret drug action in complex biological systems and quickly screen out the bioactive compounds from TCM to treat treatment of COVID-19 caused by SARS-CoV-2. Therefore, in this study, the epidemiology, TCM therapy, and the systems pharmacology-based method for TCM are reviewed for COVID-19 to provide a perspective for the prevention and treatment of SARS-CoV-2 infection. Further efforts should be made to reduce disease burden and improve the ability to design antiviral drugs and vaccines, which will benefit the health care system, economic development and even social stability.


Assuntos
COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Antivirais/administração & dosagem , COVID-19/prevenção & controle , COVID-19/virologia , Humanos , Medicina Tradicional Chinesa , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia
16.
Cells ; 10(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200372

RESUMO

Coronaviruses such as SARS-CoV-2, which is responsible for COVID-19, depend on virus spike protein binding to host cell receptors to cause infection. The SARS-CoV-2 spike protein binds primarily to ACE2 on target cells and is then processed by membrane proteases, including TMPRSS2, leading to viral internalisation or fusion with the plasma membrane. It has been suggested, however, that receptors other than ACE2 may be involved in virus binding. We have investigated the interactions of recombinant versions of the spike protein with human epithelial cell lines that express low/very low levels of ACE2 and TMPRSS2 in a proxy assay for interaction with host cells. A tagged form of the spike protein containing the S1 and S2 regions bound in a temperature-dependent manner to all cell lines, whereas the S1 region alone and the receptor-binding domain (RBD) interacted only weakly. Spike protein associated with cells independently of ACE2 and TMPRSS2, while RBD required the presence of high levels of ACE2 for interaction. As the spike protein has previously been shown to bind heparin, a soluble glycosaminoglycan, we tested the effects of various heparins on ACE2-independent spike protein interaction with cells. Unfractionated heparin inhibited spike protein interaction with an IC50 value of <0.05 U/mL, whereas two low-molecular-weight heparins were less effective. A mutant form of the spike protein, lacking the arginine-rich putative furin cleavage site, interacted only weakly with cells and had a lower affinity for unfractionated and low-molecular-weight heparin than the wild-type spike protein. This suggests that the furin cleavage site might also be a heparin-binding site and potentially important for interactions with host cells. The glycosaminoglycans heparan sulphate and dermatan sulphate, but not chondroitin sulphate, also inhibited the binding of spike protein, indicating that it might bind to one or both of these glycosaminoglycans on the surface of target cells.


Assuntos
Enzima de Conversão de Angiotensina 2/fisiologia , Células Epiteliais/metabolismo , Heparina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Células A549 , Enzima de Conversão de Angiotensina 2/genética , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Dermatan Sulfato/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Glicosaminoglicanos/farmacologia , Células HEK293 , Células HaCaT , Heparitina Sulfato/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Células Vero , Internalização do Vírus/efeitos dos fármacos
17.
Cells ; 10(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200500

RESUMO

The host nucleocytoplasmic trafficking system is often hijacked by viruses to accomplish their replication and to suppress the host immune response. Viruses encode many factors that interact with the host nuclear transport receptors (NTRs) and the nucleoporins of the nuclear pore complex (NPC) to access the host nucleus. In this review, we discuss the viral factors and the host factors involved in the nuclear import and export of viral components. As nucleocytoplasmic shuttling is vital for the replication of many viruses, we also review several drugs that target the host nuclear transport machinery and discuss their feasibility for use in antiviral treatment.


Assuntos
Núcleo Celular/metabolismo , Núcleo Celular/virologia , SARS-CoV-2/fisiologia , Fenômenos Fisiológicos Virais , Replicação Viral/fisiologia , Transporte Ativo do Núcleo Celular/fisiologia , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Internalização do Vírus , Vírus/patogenicidade
18.
Cells ; 10(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200572

RESUMO

The implications of the microbiome on Coronavirus disease 2019 (COVID-19) prognosis has not been thoroughly studied. In this study we aimed to characterize the lung and blood microbiome and their implication on COVID-19 prognosis through analysis of peripheral blood mononuclear cell (PBMC) samples, lung biopsy samples, and bronchoalveolar lavage fluid (BALF) samples. In all three tissue types, we found panels of microbes differentially abundant between COVID-19 and normal samples correlated to immune dysregulation and upregulation of inflammatory pathways, including key cytokine pathways such as interleukin (IL)-2, 3, 5-10 and 23 signaling pathways and downregulation of anti-inflammatory pathways including IL-4 signaling. In the PBMC samples, six microbes were correlated with worse COVID-19 severity, and one microbe was correlated with improved COVID-19 severity. Collectively, our findings contribute to the understanding of the human microbiome and suggest interplay between our identified microbes and key inflammatory pathways which may be leveraged in the development of immune therapies for treating COVID-19 patients.


Assuntos
COVID-19/diagnóstico , Leucócitos Mononucleares/microbiologia , Pulmão/microbiologia , Microbiota/fisiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/imunologia , COVID-19/microbiologia , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Leucócitos Mononucleares/virologia , Biópsia Líquida , Pulmão/patologia , Pulmão/virologia , Microbiota/genética , Microbiota/imunologia , Prognóstico , RNA Bacteriano/análise , RNA Fúngico/análise , RNA-Seq , SARS-CoV-2/fisiologia
19.
Cells ; 10(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201214

RESUMO

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/fisiologia , Basigina/fisiologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Células A549 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Basigina/antagonistas & inibidores , Basigina/genética , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Células Hep G2 , Interações Hospedeiro-Patógeno , Humanos , Terapia de Alvo Molecular , Interferência de RNA/fisiologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Receptores Virais/metabolismo , Receptores Virais/fisiologia , SARS-CoV-2/metabolismo , Células Vero , Tropismo Viral/fisiologia
20.
Cells ; 10(6)2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204705

RESUMO

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA-lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA-lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.


Assuntos
COVID-19/complicações , Redes Reguladoras de Genes , Infertilidade Masculina/virologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/genética , Biologia Computacional/métodos , Simulação por Computador , Interação Gene-Ambiente , Humanos , Infertilidade Masculina/genética , Masculino , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/fisiologia , Testículo/metabolismo , Testículo/patologia , Testículo/virologia , Internalização do Vírus
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