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2.
Signal Transduct Target Ther ; 6(1): 266, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253708

RESUMO

Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1ß and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.


Assuntos
COVID-19 , Células Endoteliais da Veia Umbilical Humana , Fatores de Transcrição Kruppel-Like/biossíntese , SARS-CoV-2 , COVID-19/genética , COVID-19/metabolismo , COVID-19/patologia , COVID-19/prevenção & controle , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/virologia , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Fatores de Transcrição Kruppel-Like/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética
3.
PLoS Pathog ; 17(7): e1009705, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34265022

RESUMO

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).


Assuntos
COVID-19/imunologia , Regulação para Baixo/imunologia , Interferon Tipo I/imunologia , Rim/imunologia , Miocárdio/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/patologia , Cricetinae , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/patologia , Rim/virologia , Masculino , Mesocricetus , Miocárdio/patologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia
5.
BMC Infect Dis ; 21(1): 677, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256735

RESUMO

BACKGROUND: SARS-CoV-2 has swept across the globe, causing millions of deaths worldwide. Though most survive, many experience symptoms of COVID-19 for months after acute infection. Successful prevention and treatment of acute COVID-19 infection and its associated sequelae is dependent on in-depth knowledge of viral pathology across the spectrum of patient phenotypes and physiologic responses. Longitudinal biobanking provides a valuable resource of clinically integrated, easily accessed, and quality-controlled samples for researchers to study differential multi-organ system responses to SARS-CoV-2 infection, post-acute sequelae of COVID-19 (PASC), and vaccination. METHODS: Adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR are actively recruited from the community or hospital settings to enroll in the Northern Colorado SARS-CoV-2 Biorepository (NoCo-COBIO). Blood, saliva, stool, nasopharyngeal specimens, and extensive clinical and demographic data are collected at 4 time points over 6 months. Patients are assessed for PASC during longitudinal follow-up by physician led symptom questionnaires and physical exams. This clinical trial registration is NCT04603677 . RESULTS: We have enrolled and collected samples from 119 adults since July 2020, with 66% follow-up rate. Forty-nine percent of participants assessed with a symptom surveillance questionnaire (N = 37 of 75) had PASC at any time during follow-up (up to 8 months post infection). Ninety-three percent of hospitalized participants developed PASC, while 23% of those not requiring hospitalization developed PASC. At 90-174 days post SARS-CoV-2 diagnosis, 67% of all participants had persistent symptoms (N = 37 of 55), and 85% percent of participants who required hospitalization during initial infection (N = 20) still had symptoms. The most common symptoms reported after 15 days of infection were fatigue, loss of smell, loss of taste, exercise intolerance, and cognitive dysfunction. CONCLUSIONS: Patients who were hospitalized for COVID-19 were significantly more likely to have PASC than those not requiring hospitalization, however 23% of patients who were not hospitalized also developed PASC. This patient-matched, multi-matrix, longitudinal biorepository from COVID-19 survivors with and without PASC will allow for current and future research to better understand the pathophysiology of disease and to identify targeted interventions to reduce risk for PASC. Registered 27 October 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04603677 .


Assuntos
Bancos de Espécimes Biológicos , Teste para COVID-19/métodos , COVID-19/complicações , SARS-CoV-2/genética , Sobreviventes , Adulto , Idoso , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/virologia , Colorado/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Hospitalização , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Manejo de Espécimes , Adulto Jovem
6.
Cells ; 10(7)2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201847

RESUMO

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.


Assuntos
COVID-19/patologia , Morte Celular/fisiologia , SARS-CoV-2/patogenicidade , Apoptose/fisiologia , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/metabolismo , Humanos , Necroptose/fisiologia , Internalização do Vírus
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.
Int J Mol Sci ; 22(13)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209673

RESUMO

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04-5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.


Assuntos
Proteína C9orf72/genética , COVID-19/patologia , Repetições de Microssatélites , Adulto , Fatores Etários , Idoso , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , COVID-19/genética , COVID-19/virologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
10.
Sci Immunol ; 6(61)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210785

RESUMO

A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αß T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Masculino
11.
Front Immunol ; 12: 673723, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211468

RESUMO

Reprogramming of primary virus-infected cells is the critical step that turns viral attacks harmful to humans by initiating super-spreading at cell, organism and population levels. To develop early anti-viral therapies and proactive administration, it is important to understand the very first steps of this process. Plant somatic embryogenesis (SE) is the earliest and most studied model for de novo programming upon severe stress that, in contrast to virus attacks, promotes individual cell and organism survival. We argued that transcript level profiles of target genes established from in vitro SE induction as reference compared to virus-induced profiles can identify differential virus traits that link to harmful reprogramming. To validate this hypothesis, we selected a standard set of genes named 'ReprogVirus'. This approach was recently applied and published. It resulted in identifying 'CoV-MAC-TED', a complex trait that is promising to support combating SARS-CoV-2-induced cell reprogramming in primary infected nose and mouth cells. In this perspective, we aim to explain the rationale of our scientific approach. We are highlighting relevant background knowledge on SE, emphasize the role of alternative oxidase in plant reprogramming and resilience as a learning tool for designing human virus-defense strategies and, present the list of selected genes. As an outlook, we announce wider data collection in a 'ReprogVirus Platform' to support anti-viral strategy design through common efforts.


Assuntos
COVID-19/prevenção & controle , Técnicas de Reprogramação Celular/métodos , Técnicas de Embriogênese Somática de Plantas/métodos , SARS-CoV-2/genética , COVID-19/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica de Plantas/genética , Humanos , Proteínas Mitocondriais/metabolismo , Oxirredutases/metabolismo , Desenvolvimento Vegetal/genética , Proteínas de Plantas/metabolismo , Plantas/embriologia , Plantas/genética , Espécies Reativas de Oxigênio/metabolismo
12.
Front Immunol ; 12: 687534, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220842

RESUMO

The clinical significance of antiphospholipid antibodies (aPL) in the context of infections has attracted attention since their first discovery in patients with syphilis. In fact, the recognition of aPL in patients with infections has been described in parallel to the understating of the syndrome. Since the first description of aPL-positive tests in three patients with COVID-19 diagnosed in January 2020 in Wuhan, China, a large number of studies took part in the ongoing debate on SARS-2-Cov 2 induced coagulopathy, and many following reports speculated a potential role for aPL. In order to get further insights on the effective role of detectable aPL in the pro-thrombotic status observed in COVID-19 patients, we performed an observational age-sex controlled study to compare the aPL profile of hospitalized patients with COVID with those observed in a) patients with thrombotic APS and b) patients with cultural/serologically-proved infections. Our data showed positive aPL testing in about half of the patients (53%) with COVID-19 and patients with other viral/bacterial infections (49%). However, aPL profile was different when comparing patients with overt APS and patients with aPL detected in the contest of infections. Caution is therefore required in the interpretation and generalization of the role of aPL s in the management of patients with COVID-19. Before introducing aPL testing as a part of the routine testing in patients with COVID-19, larger well-designed clinical studies are required. While the pro-thrombotic status in patients with COVID-19 is now unquestionable, different mechanisms other than aPL should be further investigated.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/patologia , Infecções Bacterianas/patologia , COVID-19/patologia , Coagulação Intravascular Disseminada/patologia , Viroses/patologia , Idoso , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/imunologia , Infecções Bacterianas/complicações , COVID-19/complicações , COVID-19/imunologia , Coagulação Intravascular Disseminada/virologia , Feminino , Humanos , Masculino , SARS-CoV-2/imunologia , Viroses/complicações
13.
Front Immunol ; 12: 649359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220807

RESUMO

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.


Assuntos
COVID-19/patologia , Leptina/imunologia , Obesidade/patologia , SARS-CoV-2/imunologia , Adipócitos/metabolismo , Células Apresentadoras de Antígenos/imunologia , COVID-19/mortalidade , Citocinas/imunologia , Suscetibilidade a Doenças/patologia , Humanos , Leptina/sangue , Monócitos/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Células Th1/imunologia
14.
Front Immunol ; 12: 688758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220846

RESUMO

Coronaviruses (CoVs) are a known global threat, and most recently the ongoing COVID-19 pandemic has claimed more than 2 million human lives. Delays and interference with IFN responses are closely associated with the severity of disease caused by CoV infection. As the most abundant viral protein in infected cells just after the entry step, the CoV nucleocapsid (N) protein likely plays a key role in IFN interruption. We have conducted a comprehensive comparative analysis and report herein that the N proteins of representative human and animal CoVs from four different genera [swine acute diarrhea syndrome CoV (SADS-CoV), porcine epidemic diarrhea virus (PEDV), severe acute respiratory syndrome CoV (SARS-CoV), SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), infectious bronchitis virus (IBV) and porcine deltacoronavirus (PDCoV)] suppress IFN responses by multiple strategies. In particular, we found that the N protein of SADS-CoV interacted with RIG-I independent of its RNA binding activity, mediating K27-, K48- and K63-linked ubiquitination of RIG-I and its subsequent proteasome-dependent degradation, thus inhibiting the host IFN response. These data provide insight into the interaction between CoVs and host, and offer new clues for the development of therapies against these important viruses.


Assuntos
Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Proteína DEAD-box 58/metabolismo , Interferons/antagonistas & inibidores , Interferons/imunologia , Receptores Imunológicos/metabolismo , Sequência de Aminoácidos/genética , Animais , COVID-19/patologia , Proteína DEAD-box 58/imunologia , Deltacoronavirus/genética , Deltacoronavirus/imunologia , Humanos , Vírus da Bronquite Infecciosa/genética , Vírus da Bronquite Infecciosa/imunologia , Fator Regulador 3 de Interferon/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Fosforilação , Vírus da Diarreia Epidêmica Suína/genética , Vírus da Diarreia Epidêmica Suína/imunologia , Receptores Imunológicos/imunologia , Vírus da SARS/genética , Vírus da SARS/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Suínos , Ubiquitinação/fisiologia
15.
Front Immunol ; 12: 697405, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220859

RESUMO

Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.


Assuntos
COVID-19/patologia , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Biomarcadores , Humanos , Inflamação/imunologia , Inflamação/patologia , Índice de Gravidade de Doença
17.
Cell Commun Signal ; 19(1): 73, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238338

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand-receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. METHODS: A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand-receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1ß, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. RESULTS: Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand-receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. CONCLUSIONS: Our study showed that macrophages driving ligand-receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1ß, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. TRIAL REGISTRATION: This is a retrospective observational study without a trial registration number. Video Abstract.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Comunicação Celular , Macrófagos/imunologia , Análise de Célula Única , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19/epidemiologia , COVID-19/fisiopatologia , China/epidemiologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas , Estudos Retrospectivos , Análise de Sequência de RNA , Índice de Gravidade de Doença
18.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198800

RESUMO

COVID-19 pandemic is caused by betacoronavirus SARS-CoV-2. The genome of this virus is composed of a single strand of RNA with 5' and 3'-UTR flanking a region of protein-coding ORFs closely resembling cells' mRNAs. MicroRNAs are endogenous post-transcriptional regulators that target mRNA to modulate protein expression and mediate cellular functions, including antiviral defense. In the present study, we carried out a bioinformatics screening to search for endogenous human microRNAs targeting the 3'-UTR of SARS-CoV-2. Results from the computational techniques allowed us to identify 10 potential candidates. The capacity of 3 of them, together with hsa-miR-138-5p, to target the SARS-CoV-2 3'-UTR was validated in vitro by gene reporter assays. Available information indicates that two of these microRNAs, namely, hsa-miR-3941 and hsa-miR-138-5p, combine effective targeting of SARS-CoV-2 genome with complementary antiviral or protective effects in the host cells that make them potential candidates for therapeutic treatment of most, if not all, COVID-19 variants known to date. All information obtained while conducting the present analysis is available at Open Science Framework repository.


Assuntos
MicroRNAs/metabolismo , SARS-CoV-2/genética , Regiões 3' não Traduzidas , Sequência de Bases , Sítios de Ligação , COVID-19/genética , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Genes Reporter , Genoma Viral , Humanos , MicroRNAs/química , Fases de Leitura Aberta , SARS-CoV-2/isolamento & purificação , Alinhamento de Sequência
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 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205262

RESUMO

COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first line of defense in a viral infection. However, a disturbed and over-activated immune response may be counterproductive, causing damage to the body. Severely ill patients hospitalised with COVID-19 exhibit increased levels of many cytokines, including Interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF). Increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. This review focuses on a Th17 pathway in the course of the immune response in COVID-19, and explores plausible targets for therapeutic intervention.


Assuntos
COVID-19/imunologia , Imunidade Celular/fisiologia , Células Th17/fisiologia , COVID-19/patologia , COVID-19/terapia , Citocinas/metabolismo , Humanos , Imunoterapia Adotiva/métodos , SARS-CoV-2/imunologia , Células Th17/metabolismo
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