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1.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467988

RESUMO

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Assuntos
COVID-19/imunologia , Interferon Tipo I/imunologia , Interferon gama/imunologia , Interferons/imunologia , COVID-19/sangue , Quimiocinas/sangue , Citocinas/sangue , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon gama/sangue , Interferon gama/genética , Interferons/sangue , Leucócitos Mononucleares/imunologia , SARS-CoV-2/isolamento & purificação
3.
Science ; 373(6552)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437126

RESUMO

Activation of cell-autonomous defense by the immune cytokine interferon-γ (IFN-γ) is critical to the control of life-threatening infections in humans. IFN-γ induces the expression of hundreds of host proteins in all nucleated cells and tissues, yet many of these proteins remain uncharacterized. We screened 19,050 human genes by CRISPR-Cas9 mutagenesis and identified IFN-γ-induced apolipoprotein L3 (APOL3) as a potent bactericidal agent protecting multiple non-immune barrier cell types against infection. Canonical apolipoproteins typically solubilize mammalian lipids for extracellular transport; APOL3 instead targeted cytosol-invasive bacteria to dissolve their anionic membranes into human-bacterial lipoprotein nanodiscs detected by native mass spectrometry and visualized by single-particle cryo-electron microscopy. Thus, humans have harnessed the detergent-like properties of extracellular apolipoproteins to fashion an intracellular lysin, thereby endowing resident nonimmune cells with a mechanism to achieve sterilizing immunity.


Assuntos
Apolipoproteínas L/metabolismo , Membrana Celular/metabolismo , Citosol/microbiologia , Bactérias Gram-Negativas/fisiologia , Interferon gama/imunologia , Apolipoproteínas L/química , Apolipoproteínas L/genética , Membrana Externa Bacteriana/metabolismo , Bacteriólise , Sistemas CRISPR-Cas , Membrana Celular/química , Membrana Celular/ultraestrutura , Permeabilidade da Membrana Celular , Células Cultivadas , Detergentes/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Edição de Genes , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Negativas/ultraestrutura , Humanos , Imunidade Inata , Lipoproteínas/química , Viabilidade Microbiana , Antígenos O/metabolismo , Domínios Proteicos , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Salmonella typhimurium/fisiologia , Salmonella typhimurium/ultraestrutura , Solubilidade
4.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
5.
Viruses ; 13(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34452355

RESUMO

BACKGROUND: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. METHODS: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. RESULTS: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA-CCR7- phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. CONCLUSION: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Memória Imunológica , Interferon gama/imunologia , Leucócitos Mononucleares/imunologia , SARS-CoV-2/imunologia , COVID-19/virologia , Epitopos de Linfócito T/imunologia , Humanos , Leucócitos Mononucleares/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Linfócitos T Citotóxicos/imunologia
6.
Front Immunol ; 12: 623087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262557

RESUMO

Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. Clinical Trial Registration: https://www.isrctn.com, identifier (ISRCTN 73114576).


Assuntos
Proliferação de Células/efeitos dos fármacos , Colecalciferol/administração & dosagem , Colecalciferol/imunologia , Interferon gama/análise , Estações do Ano , Linfócitos T Reguladores/imunologia , Adulto , Colecalciferol/sangue , Colecalciferol/farmacologia , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Inflamação/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/análise , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Luz Solar , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/fisiologia
7.
Cytokine ; 146: 155637, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34242899

RESUMO

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Interferon gama/imunologia , Antivirais/imunologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , Interferon gama/uso terapêutico , Receptores de Interferon/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Transdução de Sinais/imunologia
8.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207474

RESUMO

Chicken meat is often a major component of a modern diet. Allergy to chicken meat is relatively rare and occurs independently or in subjects allergic to ovalbumin (OVA). We examined the effect of adoptive transfer of OVA-CD4+ T cells on the immune response to OVA in mice fed chicken meat. Donor mice were injected intraperitoneally with 100 µg of OVA with Freund's adjuvant two times over a week, and CD4+ T cells were isolated from them and transferred to naïve mice (CD4+/OVA/ChM group), which were then provoked with OVA with FA and fed freeze-dried chicken meat for 14 days. The mice injected with OVA and fed chicken meat (OVA/ChM group), and sensitized (OVA group) and healthy (PBS group) mice served as controls. Humoral and cellular response to OVA was monitored over the study. The CD4+/OVA/ChM group had lowered levels of anti-OVA IgG and IgA, and total IgE. There were significant differences in CD4+, CD4+CD25+, and CD4+CD25+Foxp3+ T cells between groups. OVA stimulation decreased the splenocyte proliferation index and IFN-γ secretion in the CD4+/OVA/ChM group compared to the OVA group. IL-4 was increased in the OVA/ChM mice, which confirms allergenic potential of the egg-meat protein combination. Transfer of OVA-experienced CD4+ T cells ameliorated the negative immune response to OVA.


Assuntos
Transferência Adotiva , Alérgenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunoglobulinas/imunologia , Ovalbumina/imunologia , Produtos Avícolas , Animais , Proteínas Aviárias/imunologia , Células Cultivadas , Galinhas , Feminino , Hipersensibilidade Alimentar/imunologia , Interferon gama/imunologia , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C
9.
BMC Pediatr ; 21(1): 317, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271894

RESUMO

BACKGROUND: Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. METHODS: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. RESULTS: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = - 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = - 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 µmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. CONCLUSIONS: PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.


Assuntos
Linfócitos T CD8-Positivos , Interferon gama/imunologia , Receptor de Morte Celular Programada 1 , Animais , Animais Recém-Nascidos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Humanos , Lactente , Fígado , Camundongos , Camundongos Endogâmicos BALB C
10.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070750

RESUMO

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Matriz Extracelular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Cultura de Células , Módulo de Elasticidade , Matriz Extracelular/química , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Hidrogéis/química , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mecanotransdução Celular , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Reologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia
11.
Front Immunol ; 12: 599805, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079535

RESUMO

Background: Dengue virus (DENV) infection has a global impact on public health. The clinical outcomes (of DENV) can vary from a flu-like illness called dengue fever (DF), to a more severe form, known as dengue hemorrhagic fever (DHF). The underlying innate immune mechanisms leading to protective or detrimental outcomes have not been fully elucidated. Helper innate lymphoid cells (hILCs), an innate lymphocyte recently discovered, functionally resemble T-helper cells and are important in inflammation and homeostasis. However, the role of hILCs in DENV infection had been unexplored. Methods: We performed flow cytometry to investigate the frequency and phenotype of hILCs in peripheral blood mononuclear cells from DENV-infected patients of different disease severities (DF and DHF), and at different phases (febrile and convalescence) of infection. Intracellular cytokine staining of hILCs from DF and DHF were also evaluated by flow cytometry after ex vivo stimulation. Further, the hILCs were sorted and subjected to transcriptome analysis using RNA sequencing. Differential gene expression analysis was performed to compare the febrile and convalescent phase samples in DF and DHF. Selected differentially expressed genes were then validated by quantitative PCR. Results: Phenotypic analysis showed marked activation of all three hILC subsets during the febrile phase as shown by higher CD69 expression when compared to paired convalescent samples, although the frequency of hILCs remained unchanged. Upon ex vivo stimulation, hILCs from febrile phase DHF produced significantly higher IFN-γ and IL-4 when compared to those of DF. Transcriptomic analysis showed unique hILCs gene expression in DF and DHF, suggesting that divergent functions of hILCs may be associated with different disease severities. Differential gene expression analysis indicated that hILCs function both in cytokine secretion and cytotoxicity during the febrile phase of DENV infection. Conclusions: Helper ILCs are activated in the febrile phase of DENV infection and display unique transcriptomic changes as well as cytokine production that correlate with severity. Targeting hILCs during early innate response to DENV might help shape subsequent immune responses and potentially lessen the disease severity in the future.


Assuntos
Vírus da Dengue/imunologia , Dengue/imunologia , Imunidade Inata , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/imunologia , Dengue/patologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , Linfócitos T Auxiliares-Indutores/patologia
12.
BMC Infect Dis ; 21(1): 587, 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34144700

RESUMO

BACKGROUND: Talaromyces marneffei (T. marneffei) infection has been associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We aimed to investigate the clinical features of non-HIV-infected patients with T. marneffei infection in southern China. METHODS: Between January 2018 and September 2020, we enrolled patients with T. marneffei infection who were HIV-negative (group TM, n = 42), including anti-IFN-γ autoantibody-positive (group TMP, n = 22) and anti-IFN-γ autoantibody-negative (group TMN, n = 20) patients and healthy controls (group HC, n = 40). Anti-IFN-γ autoantibodies were detected by ELISA. Clinical characteristics and clinical laboratory parameters were recorded. RESULTS: Compared with anti-IFN-γ autoantibody-negative patients with T. marneffei infection, anti-IFN-γ autoantibody-positive patients did not have underlying respiratory disease; more frequently exhibited dissemination of systemic infections with severe pleural effusion; had higher WBC counts, C-reactive protein levels, erythrocyte sedimentation rates, and neutrophil and CD8+ T cell counts; had lower hemoglobin levels; and were more likely to have other intracellular pathogen infections. Most of these patients had poor outcomes despite standardized antimicrobial therapy. CONCLUSION: T. marneffei-infected patients with higher anti-IFN-γ autoantibody titers have more severe disease and complex clinical conditions.


Assuntos
Síndromes de Imunodeficiência/etiologia , Interferon gama/imunologia , Micoses/imunologia , Adulto , Autoanticorpos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença
13.
Nature ; 596(7872): 417-422, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34192737

RESUMO

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.


Assuntos
Envelhecimento/imunologia , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Pessoal de Saúde , Humanos , Imunidade/genética , Imunização Secundária , Imunoglobulina A/imunologia , Switching de Imunoglobulina , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Inflamação/sangue , Inflamação/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
14.
Int J Med Sci ; 18(12): 2561-2569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104087

RESUMO

SARS-CoV-2 infection poses a global challenge to human health. Upon viral infection, host cells initiate the innate antiviral response, which primarily involves type I interferons (I-IFNs), to enable rapid elimination of the invading virus. Previous studies revealed that SARS-CoV-2 infection limits the expression of I-IFNs in vitro and in vivo, but the underlying mechanism remains incompletely elucidated. In the present study, we performed data mining and longitudinal data analysis using SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells and ferrets, and the results confirmed the strong inhibitory effect of SARS-CoV-2 on the induction of I-IFNs. Moreover, we identified genes that are negatively correlated with IFNB1 expression in vitro and in vivo based on Pearson correlation analysis. We found that SARS-CoV-2 activates numerous intrinsic pathways, such as the circadian rhythm, phosphatidylinositol signaling system, peroxisome, and TNF signaling pathways, to inhibit I-IFNs. These intrinsic inhibitory pathways jointly facilitate the successful immune evasion of SARS-CoV-2. Our study elucidates the underlying mechanism by which SARS-CoV-2 evades the host innate antiviral response in vitro and in vivo, providing theoretical evidence for targeting these immune evasion-associated pathways to combat SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interferon gama/metabolismo , SARS-CoV-2/imunologia , Animais , Brônquios/citologia , COVID-19/virologia , Linhagem Celular , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Células Epiteliais , Furões , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata , Interferon gama/imunologia , RNA-Seq , Mucosa Respiratória/citologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
15.
Front Immunol ; 12: 688436, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093595

RESUMO

Background: Adaptive immune responses to structural proteins of the virion play a crucial role in protection against coronavirus disease 2019 (COVID-19). We therefore studied T cell responses against multiple SARS-CoV-2 structural proteins in a large cohort using a simple, fast, and high-throughput approach. Methods: An automated interferon gamma release assay (IGRA) for the Nucleocapsid (NC)-, Membrane (M)-, Spike-C-terminus (SCT)-, and N-terminus-protein (SNT)-specific T cell responses was performed using fresh whole blood from study subjects with convalescent, confirmed COVID-19 (n = 177, more than 200 days post infection), exposed household members (n = 145), and unexposed controls (n = 85). SARS-CoV-2-specific antibodies were assessed using Elecsys® Anti-SARS-CoV-2 (Ro-N-Ig) and Anti-SARS-CoV-2-ELISA (IgG) (EI-S1-IgG). Results: 156 of 177 (88%) previously PCR confirmed cases were still positive by Ro-N-Ig more than 200 days after infection. In T cells, most frequently the M-protein was targeted by 88% seropositive, PCR confirmed cases, followed by SCT (85%), NC (82%), and SNT (73%), whereas each of these antigens was recognized by less than 14% of non-exposed control subjects. Broad targeting of these structural virion proteins was characteristic of convalescent SARS-CoV-2 infection; 68% of all seropositive individuals targeted all four tested antigens. Indeed, anti-NC antibody titer correlated loosely, but significantly with the magnitude and breadth of the SARS-CoV-2-specific T cell response. Age, sex, and body mass index were comparable between the different groups. Conclusion: SARS-CoV-2 seropositivity correlates with broad T cell reactivity of the structural virus proteins at 200 days after infection and beyond. The SARS-CoV-2-IGRA can facilitate large scale determination of SARS-CoV-2-specific T cell responses with high accuracy against multiple targets.


Assuntos
COVID-19/imunologia , Interferon gama/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Proteínas Estruturais Virais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/sangue , Feminino , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169908

RESUMO

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/farmacologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Progressão da Doença , Farmacorresistência Viral , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Inibidores de Janus Quinases/farmacologia , Recidiva
17.
Parasitol Res ; 120(7): 2303-2309, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34110502

RESUMO

Toxoplasma gondii is an intracellular protozoan parasite that can remarkably infect, survive, and replicate in almost all mammalian cells and can cause severe neurological and ocular damage in immunocompromised individuals. It is known that Natural Killer cells (NK cells), as a type of cytotoxic lymphocyte, have critical protective roles in innate immunity during the T. gondii infection through releasing interferon gamma (IFN-γ). Interleukin 12 (IL-12) is a pivotal critical cytokine for the generation of IFN-γ-producing NK cells. Several studies have shown cytokines' impact on NK cell activation; and IL-2 has an important role with a potent stimulatory factor for NK cells. In this review, we summarized the mechanism of interleukin-12 production stimulation by T. gondii tachyzoites and discussed several factors affecting this mechanism.


Assuntos
Interleucina-12/fisiologia , Células Matadoras Naturais/imunologia , Toxoplasma/fisiologia , Toxoplasmose/imunologia , Animais , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Interferon gama/imunologia , Interferon gama/metabolismo , Toxoplasma/imunologia
18.
Front Immunol ; 12: 632304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953709

RESUMO

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1-22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1-22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.


Assuntos
Vacinas Bacterianas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/imunologia , Lipídeos/imunologia , Listeria/imunologia , Mycobacterium/imunologia , RNA Mensageiro/imunologia , Streptococcus/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteção Cruzada , Reações Cruzadas , Células Dendríticas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Interferon gama/imunologia , Lipídeos/química , Listeria/enzimologia , Listeria/genética , Camundongos , RNA Mensageiro/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
19.
Nat Commun ; 12(1): 3010, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021148

RESUMO

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Memória Imunológica/imunologia , Pulmão/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/virologia , Movimento Celular/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/virologia , SARS-CoV-2/fisiologia , Linfócitos T/metabolismo
20.
Nat Commun ; 12(1): 2715, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976157

RESUMO

Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.


Assuntos
Envelhecimento/genética , Divisão Celular Assimétrica/genética , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/genética , Serina-Treonina Quinases TOR/genética , Envelhecimento/imunologia , Animais , Divisão Celular Assimétrica/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia
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