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1.
Methods Mol Biol ; 2380: 201-209, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802133

RESUMO

Generation of effective immune protection against viral infection and vaccination depends greatly on a successful engagement and stimulation of adaptive immune B cells and a specialized CD4+ T cell subset called T follicular helper cells (TFH cells). Since TFH cells primarily reside in lymphoid tissues, they can be challenging to study in human settings. However, a counterpart of these cells, circulating TFH (cTFH) cells, can be detected in peripheral blood. Assessment of cTFH cells serves as an informative marker of humoral responses following viral infection and vaccination and can be predictive of antibody titers. Here, we describe a comprehensive flow cytometry detection method for dissecting cTFH subsets and activation, together with the assessment of antibody-secreting cells (ASCs), from a small volume of human whole blood. This approach allows the investigation of cellular events that underpin successful immune responses following influenza and SARS-CoV-2 infection/vaccination in humans and is applicable to other viral disease settings.


Assuntos
Linfócitos B/imunologia , COVID-19 , Influenza Humana , Células T Auxiliares Foliculares/imunologia , COVID-19/imunologia , Humanos , Influenza Humana/imunologia
2.
PLoS Comput Biol ; 17(12): e1009664, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34898597

RESUMO

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.


Assuntos
Evolução Molecular , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Antivirais/biossíntese , Antígenos Virais/química , Antígenos Virais/genética , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Biologia Computacional , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Evasão da Resposta Imune/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Modelos Imunológicos , Simulação de Dinâmica Molecular , Mutação , Pandemias , Glicoproteína da Espícula de Coronavírus/química , Proteínas do Envelope Viral/química
3.
Sci Rep ; 11(1): 21519, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728719

RESUMO

A high neutrophil to lymphocyte ratio (NLR) is considered an unfavorable prognostic factor in various diseases, including COVID-19. The prognostic value of NLR in other respiratory viral infections, such as Influenza, has not hitherto been extensively studied. We aimed to compare the prognostic value of NLR in COVID-19, Influenza and Respiratory Syncytial Virus infection (RSV). A retrospective cohort of COVID-19, Influenza and RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020 was analyzed. Laboratory, demographic, and clinical parameters were collected. Two way analyses of variance (ANOVA) was used to compare the association between NLR values and poor outcomes among the three groups. ROC curve analyses for each virus was applied to test the discrimination ability of NLR. 722 COVID-19, 2213 influenza and 482 RSV patients were included. Above the age of 50, NLR at admission was significantly lower among COVID-19 patients (P < 0.001). NLR was associated with poor clinical outcome only in the COVID-19 group. ROC curve analysis was performed; the area under curve of poor outcomes for COVID-19 was 0.68, compared with 0.57 and 0.58 for Influenza and RSV respectively. In the COVID-19 group, multivariate logistic regression identified a high NLR (defined as a value above 6.82) to be a prognostic factor for poor clinical outcome, after adjusting for age, sex and Charlson comorbidity score (odds ratio of 2.9, P < 0.001). NLR at admission is lower and has more prognostic value in COVID-19 patients, when compared to Influenza and RSV.


Assuntos
COVID-19/patologia , Influenza Humana/patologia , Infecções por Vírus Respiratório Sincicial/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , COVID-19/imunologia , COVID-19/virologia , Feminino , Humanos , Influenza Humana/imunologia , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/metabolismo , Prognóstico , Curva ROC , Infecções por Vírus Respiratório Sincicial/imunologia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação
4.
Front Immunol ; 12: 770066, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777390

RESUMO

Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient's history of health, and new therapeutic options identified.


Assuntos
COVID-19/imunologia , Inflamação/imunologia , Vírus da Influenza A , Influenza Humana/imunologia , Obesidade/imunologia , SARS-CoV-2 , Animais , Humanos , Índice de Gravidade de Doença
5.
Sci Rep ; 11(1): 22164, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34773048

RESUMO

The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.


Assuntos
Vírus da Influenza A/imunologia , Vacinas contra Influenza/uso terapêutico , Interferon Tipo I/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas Atenuadas/uso terapêutico , Proteínas não Estruturais Virais/imunologia , Imunidade Adaptativa , Animais , COVID-19/imunologia , COVID-19/prevenção & controle , Galinhas , Deleção de Genes , Humanos , Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas não Estruturais Virais/genética
6.
JCI Insight ; 6(22)2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34618691

RESUMO

BACKGROUNDInfluenza A virus (IAV) and SARS-CoV-2 are pandemic viruses causing millions of deaths, yet their clinical manifestations are distinctly different.METHODSWith the hypothesis that upper airway immune and epithelial cell responses are also distinct, we performed single-cell RNA sequencing (scRNA-Seq) on nasal wash cells freshly collected from adults with either acute COVID-19 or influenza or from healthy controls. We focused on major cell types and subtypes in a subset of donor samples.ResultsNasal wash cells were enriched for macrophages and neutrophils for both individuals with influenza and those with COVID-19 compared with healthy controls. Hillock-like epithelial cells, M2-like macrophages, and age-dependent B cells were enriched in COVID-19 samples. A global decrease in IFN-associated transcripts in neutrophils, macrophages, and epithelial cells was apparent in COVID-19 samples compared with influenza samples. The innate immune response to SARS-CoV-2 appears to be maintained in macrophages, despite evidence for limited epithelial cell immune sensing. Cell-to-cell interaction analyses revealed a decrease in epithelial cell interactions in COVID-19 and highlighted differences in macrophage-macrophage interactions for COVID-19 and influenza.ConclusionsOur study demonstrates that scRNA-Seq can define host and viral transcriptional activity at the site of infection and reveal distinct local epithelial and immune cell responses for COVID-19 and influenza that may contribute to their divergent disease courses.FundingMassachusetts Consortium on Pathogen Readiness, the Mathers Foundation, and the Department of Defense (W81XWH2110029) "COVID-19 Expansion for AIRe Program."


Assuntos
COVID-19 , Imunidade Inata , Vírus da Influenza A , Influenza Humana , Macrófagos , RNA-Seq , SARS-CoV-2 , Adulto , COVID-19/genética , COVID-19/imunologia , Feminino , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Influenza Humana/genética , Influenza Humana/imunologia , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Lavagem Nasal , SARS-CoV-2/genética , SARS-CoV-2/imunologia
8.
Med Sci Monit ; 27: e934949, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34602605

RESUMO

There have been five viral pandemics in the past century, four were due to influenza, and the ongoing COVID-19 pandemic is due to SARS-CoV-2 infection. During the COVID-19 pandemic, there has been a 99% global reduction in the diagnosis of influenza. Also, from 2020, global mortality rates from influenza fell to record levels during the influenza seasons in the southern and northern hemispheres. However, as social restrictions become lifted and the winter season begins in the northern hemisphere, it is expected that influenza will re-emerge. The World Health Organization (WHO) FluNet surveillance platform provides global surveillance data on influenza, and the US Centers for Disease Control and Prevention (CDC) records national weekly infection rates. Both surveillance programs have identified zoonotic avian and swine influenza variants in humans. The WHO Pandemic Influenza Preparedness (PIP) Framework requires WHO Member States to share data on cases of emerging influenza viruses with pandemic potential in a regular and timely way. The WHO PIP Framework organizes the Global Influenza Surveillance and Response System (GISRS), a global network of public health laboratories developing candidate virus vaccines. This Editorial aims to present the reasons for concern regarding the emergence of pandemic influenza viruses driven by the social and public health responses to the COVID-19 pandemic and highlights the importance of global influenza surveillance at this time.


Assuntos
COVID-19/epidemiologia , Influenza Humana/epidemiologia , Orthomyxoviridae/imunologia , Pandemias , COVID-19/imunologia , Humanos , Influenza Humana/imunologia , SARS-CoV-2
10.
PLoS One ; 16(10): e0258261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644311

RESUMO

Influenza A virus (IAV) predisposes individuals to often more severe secondary bacterial infections with Streptococcus pneumonia (S. pneumoniae). The outcomes of these infections may be made worse with the increase in antimicrobial resistance and a lack of new treatments to combat this. Th17 responses are crucial in clearing S. pneumoniae from the lung. We previously demonstrated that early IAV infection of human monocytes significantly reduced levels of S. pneumoniae-driven cytokines involved in the Th17 response. Here, we have further identified that IAV targets specific TLRs (TLR2, TLR4, TLR9) involved in sensing S. pneumoniae infection resulting, in a reduction in TLR agonist-induced IL-23 and TGF-ß. The effect of IAV is more profound on the TLR2 and TLR9 pathways. We have established that IAV-mediated inhibition of TLR9-induction is related to a downregulation of RORC, a Th17 specific transcription factor. Other studies using mouse models demonstrated that TLR5 agonism improved the efficacy of antibiotics in the treatment of IAV/S. pneumoniae co-infections. Therefore, we investigated if TLR5 agonism could restore inhibited Th17 responses in human monocytes. Levels of pneumococcus-driven cytokines, which had previously been inhibited by IAV were not reduced in the presence of the TLR5 mono-agonist, suggesting that such treatment may overcome IAV inhibition of Th17 responses. The importance of our research is in demonstrating the IAV directly targets S. pneumoniae-associated TLR pathways. Additionally, the IAV-inhibition of Th17 responses can be restored by TLR5 agonism, which indicates that there may be a different Th17 signalling pathway which is not affected by IAV infection.


Assuntos
Imunidade , Influenza Humana/imunologia , Influenza Humana/virologia , Monócitos/imunologia , Monócitos/virologia , Streptococcus pneumoniae/imunologia , Receptor 5 Toll-Like/agonistas , Humanos , Imunidade/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/imunologia , Monócitos/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/farmacologia
11.
Signal Transduct Target Ther ; 6(1): 367, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34667157

RESUMO

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.


Assuntos
Síndrome da Liberação de Citocina , Transdução de Sinais/imunologia , Doença Aguda , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva/efeitos adversos , Influenza Humana/complicações , Influenza Humana/imunologia , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/terapia , Vírus da SARS/imunologia , SARS-CoV-2/imunologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/terapia
12.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34702753

RESUMO

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Testes de Inibição da Hemaglutinação/métodos , Imunogenicidade da Vacina/imunologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
13.
Nat Immunol ; 22(11): 1416-1427, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663977

RESUMO

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.


Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , SARS-CoV-2/fisiologia , Ubiquitinas/metabolismo , Diferenciação Celular , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Citocinas/genética , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Evasão da Resposta Imune , Imunidade Inata , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Células-Tronco Pluripotentes/citologia , Ubiquitinação , Ubiquitinas/genética , Zika virus/fisiologia , Infecção por Zika virus/imunologia
14.
PLoS One ; 16(10): e0258258, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34648535

RESUMO

BACKGROUND: A growing number of parents refuse vaccination due to concerns about side effects. Influenza vaccine is no exception and remains one of the most controversial vaccines. Data regarding influenza vaccine uptake and parental knowledge, attitude and practice towards vaccination in the Lebanese population is lacking. The aim of this study was to assess the rate of vaccination refusal and potential associated factors among Lebanese parents of school-aged children, in general and with a focus on influenza vaccine. METHODS: A parent questionnaire was distributed in randomly selected 2 public and 2 private schools from the greater Beirut area during the school year 2017-2018. Questionnaires covered knowledge, attitude (including themes of efficacy, hesitancy and trust), and practice of vaccination in general and influenza vaccine in particular. RESULTS: The response rate was 76.5% (306/400). Overall, 29.4% parents reported vaccinating their children against influenza (62.2% in private and 37.7% in public schools). Younger age, paternal employment and higher household income were associated with higher vaccination rates (p = 0.01, 0.02 and <0.0001 respectively). Lack of vaccine recommendation by the physician was the most common reason for not taking it (47%). Parents who accepted influenza vaccination had higher scores in efficacy, hesitancy and trust and were more compliant with other vaccinations. CONCLUSION: One third of parents of school aged children in the greater Beirut area vaccinate their children against influenza. This rate is likely lower in rural remote areas. Physician's recommendation is the single most important predictor of such vaccination. Future studies tackling physicians' attitude and practice are needed to help improve influenza vaccination rates in the Lebanese population.


Assuntos
Países em Desenvolvimento , Conhecimentos, Atitudes e Prática em Saúde , Vacinas contra Influenza/imunologia , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Pais , Vacinação , Adolescente , Comportamento , Criança , Pré-Escolar , Estudos Transversais , Humanos , Líbano , Aceitação pelo Paciente de Cuidados de Saúde , Instituições Acadêmicas , Confiança
15.
PLoS Pathog ; 17(9): e1009804, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34529726

RESUMO

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.


Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos B/imunologia , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , Estudos de Coortes , Estado Terminal/mortalidade , Feminino , Humanos , Imunofenotipagem , Influenza Humana/imunologia , Lectinas Tipo C/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/imunologia , Gravidade do Paciente
16.
Front Immunol ; 12: 681516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489933

RESUMO

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1ß were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-ß were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients.


Assuntos
COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transcriptoma/imunologia , Adulto , Idoso , Biomarcadores/sangue , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade
17.
Nutrients ; 13(9)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34579070

RESUMO

Deoxynivalenol (DON), a highly prevalent mycotoxin food contaminant, is known to have immunotoxic effects. In the current study, the potential of dietary interventions with specific mixtures of trans-galactosyl-oligosaccharides (TOS) to alleviate these effects were assessed in a murine influenza vaccination model. Vaccine-specific immune responses were measured in C57Bl/6JOlaHsd mice fed diets containing DON, TOS or a combination, starting 2 weeks before the first vaccination. The direct effects of TOS and its main oligosaccharide, 3'-galactosyl-lactose (3'-GL), on DON-induced damage were studied in Caco-2 cells, as an in vitro model of the intestinal epithelial barrier. Exposure to DON significantly reduced vaccine-specific immune responses and the percentages of Tbet+ Th1 cells and B cells in the spleen. DON significantly altered epithelial structure and integrity in the ileum and reduced the SCFA levels in the cecum. Adding TOS into DON-containing diets significantly improved vaccine-specific immune responses, restored the immune cell balance in the spleen and increased SCFA concentrations in the cecum. Incubating Caco-2 cells with TOS and 3'-GL in vitro further confirmed their protective effects against DON-induced barrier disruption, supporting immune modulation. Overall, dietary intervention with TOS can attenuate the adverse effects of DON on Th1-mediated immune responses and gut homeostasis. These beneficial properties might be linked to the high levels of 3'-GL in TOS.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Influenza Humana/imunologia , Leite Humano/química , Oligossacarídeos/farmacologia , Tricotecenos/imunologia , Trissacarídeos/farmacologia , Vacinação , Animais , Células CACO-2 , Ceco/efeitos dos fármacos , Dieta , Ácidos Graxos Voláteis/metabolismo , Feminino , Contaminação de Alimentos , Humanos , Intestinos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Micotoxinas/imunologia , Baço/efeitos dos fármacos , Células Th1/metabolismo , Vacinas/imunologia
18.
J Virol ; 95(20): e0023121, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34379499

RESUMO

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in retinoic acid-inducible gene I (RIG-I) translocation to mitochondrial antiviral-signaling protein (MAVS) to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-ß promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-ß expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C terminus-truncated NS1 with a T49A mutation dramatically increases IFN-ß mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-ß expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in retinoic acid-inducible gene I (RIG-I) translocation that induces type I interferon (IFN) expression, and that NS1 protein prevents RIG-I translocation to the mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-ß suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.


Assuntos
Proteínas 14-3-3/imunologia , Influenza Humana/imunologia , Interferon beta/metabolismo , Proteínas 14-3-3/metabolismo , Linhagem Celular Tumoral , Proteína DEAD-box 58/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/imunologia , Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Interferon beta/fisiologia , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional , RNA Viral/genética , Receptores Imunológicos/metabolismo , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/genética
19.
J Immunol ; 207(5): 1371-1376, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380647

RESUMO

Inflammatory cytokine storm is a known cause for acute respiratory distress syndrome. In this study, we have investigated the role of IFN-γ in lethal lung inflammation using a mouse model of postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. To mimic the clinical scenario, animals were treated with antibiotics for effective bacterial control following MRSA superinfection. However, antibiotic therapy alone is not sufficient to improve survival of wild-type animals in this lethal acute respiratory distress syndrome model. In contrast, antibiotics induce effective protection in mice deficient in IFN-γ response. Mechanistically, we show that rather than inhibiting bacterial clearance, IFN-γ promotes proinflammatory cytokine response to cause lethal lung damage. Neutralization of IFN-γ after influenza prevents hyperproduction of TNF-α, and thereby protects against inflammatory lung damage and animal mortality. Taken together, the current study demonstrates that influenza-induced IFN-γ drives a stepwise propagation of inflammatory cytokine response, which ultimately results in fatal lung damage during secondary MRSA pneumonia, despite of antibiotic therapy.


Assuntos
Antibacterianos/uso terapêutico , Inflamação/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Interferon gama/metabolismo , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Pneumonia Estafilocócica/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Células Cultivadas , Humanos , Influenza Humana/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/complicações , Pneumonia Estafilocócica/complicações , Infecções Estafilocócicas/complicações , Superinfecção , Fator de Necrose Tumoral alfa
20.
J Immunol ; 207(5): 1310-1321, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380652

RESUMO

The respiratory tract is constantly exposed to various airborne pathogens. Most vaccines against respiratory infections are designed for the parenteral routes of administration; consequently, they provide relatively minimal protection in the respiratory tract. A vaccination strategy that aims to induce the protective mucosal immune responses in the airway is urgently needed. The FcRn mediates IgG Ab transport across the epithelial cells lining the respiratory tract. By mimicking this natural IgG transfer, we tested whether FcRn delivers vaccine Ags to induce a protective immunity to respiratory infections. In this study, we designed a monomeric IgG Fc fused to influenza virus hemagglutinin (HA) Ag with a trimerization domain. The soluble trimeric HA-Fc were characterized by their binding with conformation-dependent HA Abs or FcRn. In wild-type, but not FcRn knockout, mice, intranasal immunization with HA-Fc plus CpG adjuvant conferred significant protection against lethal intranasal challenge with influenza A/PR/8/34 virus. Further, mice immunized with a mutant HA-Fc lacking FcRn binding sites or HA alone succumbed to lethal infection. Protection was attributed to high levels of neutralizing Abs, robust and long-lasting B and T cell responses, the presence of lung-resident memory T cells and bone marrow plasma cells, and a remarkable reduction of virus-induced lung inflammation. Our results demonstrate for the first time, to our knowledge, that FcRn can effectively deliver a trimeric viral vaccine Ag in the respiratory tract and elicit potent protection against respiratory infection. This study further supports a view that FcRn-mediated mucosal immunization is a platform for vaccine delivery against common respiratory pathogens.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/fisiologia , Receptores Fc/metabolismo , Mucosa Respiratória/metabolismo , Administração Intranasal , Animais , Anticorpos Antivirais/metabolismo , Modelos Animais de Doenças , Resistência à Doença , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/metabolismo , Vacinas contra Influenza/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Fc/genética , Mucosa Respiratória/imunologia , Vacinação
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