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1.
Signal Transduct Target Ther ; 6(1): 331, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471099

RESUMO

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.


Assuntos
COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Transdução de Sinais/imunologia , Células A549 , COVID-19/patologia , Células CACO-2 , Células HEK293 , Células Hep G2 , Humanos , Interferon Tipo I/imunologia , Fosfoproteínas/imunologia
3.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502139

RESUMO

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of the COVID19 pandemic. The SARS-CoV-2 genome encodes for a small accessory protein termed Orf9b, which targets the mitochondrial outer membrane protein TOM70 in infected cells. TOM70 is involved in a signaling cascade that ultimately leads to the induction of type I interferons (IFN-I). This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70. Binding of Orf9b to TOM70 decreases the expression of IFN-I; however, the underlying mechanism remains elusive. We show that the binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. We characterized the binding site of Orf9b within the C-terminal domain of TOM70 and found that a serine in position 53 of Orf9b and a glutamate in position 477 of TOM70 are crucial for the association of both proteins. A phosphomimetic variant Orf9bS53E showed drastically reduced binding to TOM70 and did not inhibit Hsp90 recruitment, suggesting that Orf9b-TOM70 complex formation is regulated by phosphorylation. Eventually, we identified the N-terminal TPR domain of TOM70 as a second binding site for Orf9b, which indicates a so far unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.


Assuntos
COVID-19/transmissão , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , SARS-CoV-2/patogenicidade , Animais , Sítios de Ligação/genética , COVID-19/imunologia , COVID-19/virologia , Chlorocebus aethiops , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/isolamento & purificação , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/isolamento & purificação , Mutação , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fosfoproteínas/isolamento & purificação , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica/genética , Ligação Proteica/imunologia , Domínios Proteicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Células Vero
4.
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
5.
Sci Immunol ; 6(62)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413139

RESUMO

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Interferon Tipo I/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Autoanticorpos/sangue , COVID-19/mortalidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Estado Terminal , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Interferon-alfa/imunologia , Pessoa de Meia-Idade , Adulto Jovem
6.
J Exp Med ; 218(10)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34357402

RESUMO

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Interferon Tipo I/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Animais , Antivirais/imunologia , Antivirais/farmacologia , Autoanticorpos/sangue , COVID-19/sangue , COVID-19/virologia , Chlorocebus aethiops , Feminino , Humanos , Interferon Tipo I/farmacologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/imunologia , Cavidade Nasal/virologia , Estudos Prospectivos , SARS-CoV-2/fisiologia , Células Vero , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
7.
Viruses ; 13(8)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34452484

RESUMO

Given the impact of pandemics due to viruses of bat origin, there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent based model that encompasses and bridges differences between bat and human responses to viral infection: the comparative biology immune agent based model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and type 1 interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in preparation for future viral pandemics of zoonotic origin.


Assuntos
Quirópteros/imunologia , Imunidade Inata , Viroses/imunologia , Viroses/veterinária , Animais , Quirópteros/virologia , Simulação por Computador , Endotélio/fisiologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Índice de Gravidade de Doença , Estresse Fisiológico , Zoonoses Virais , Viroses/virologia , Fenômenos Fisiológicos Virais , Eliminação de Partículas Virais
8.
Fish Shellfish Immunol ; 116: 150-160, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265416

RESUMO

As a tyrosine phosphatase, Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) serves as an inhibitor in PI3K-Akt pathway. In mammals, SHP2 can phosphorylate GSK3ß at Y216 site to control the expression of IFN. So far, the multiple functions of SHP2 have been reported in mammals. However, little is known about fish SHP2. In this study, we cloned and identified a grass carp (Ctenopharyngodon idellus) SHP2 gene (CiSHP2, MT373151). SHP2 is conserved among different vertebrates by amino acid sequences alignment and the phylogenetic tree analysis. CiSHP2 shared the closest homology with Danio rerio SHP2. Simultaneously, SHP2 was also tested in grass carp tissues and CIK (C. idellus kidney) cells. We found that it responded to poly I:C stimulation. CiSHP2 was located in the cytoplasm just as the same as those of mammals. Interestingly, it inhibited the phosphorylation level of GSK3ß in a non-contact manner. Meanwhile CiGSK3ß interacted with and directly phosphorylated CiTBK1. In addition, we found that CiSHP2 also reduced the phosphorylation level of CiTBK1 by CiGSK3ß, and then it depressed the expression of IFN I via GSK3ß-TBK1 axis. These results suggested that CiSHP2 was involved in CiGSK3ß and CiTBK1 activity but not regulated their transcriptional level. At the same time, we also found that CiSHP2 also influenced the activity of CiIRF3. Therefore, fish SHP2 inhibited IFN I expression through blocking GSK3ß-TBK1 signal axis.


Assuntos
Carpas/imunologia , Proteínas de Peixes/imunologia , Glicogênio Sintase Quinase 3 beta/imunologia , Interferon Tipo I/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/imunologia , Sequência de Aminoácidos , Animais , Carpas/genética , Linhagem Celular , Proteínas de Peixes/genética , Fosforilação , Filogenia , Poli I-C/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
9.
Front Immunol ; 12: 563336, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248923

RESUMO

The innate immune and host-protective responses to viruses, such as the airway pathogen human metapneumovirus (HMPV), depend on interferons (IFNs) that is induced through TANK-binding kinase 1 (TBK1) and IFN regulatory factors (IRFs). The transcription factor IRF1 is important for host resistance against several viruses and has a key role in induction of IFN-λ at mucosal surfaces. In most cell types IRF1 is expressed at very low levels, but its mRNA is rapidly induced when the demand for IRF1 activity arises. Despite general recognition of the importance of IRF1 to antiviral responses, the molecular mechanisms by which IRF1 is regulated during viral infections are not well understood. Here we identify the serine/threonine kinase TBK1 and IFN-ß as critical regulators of IRF1 mRNA and protein levels in human monocyte-derived macrophages. We find that inhibition of TBK1 activity either by the semi-selective TBK1/IKKε inhibitor BX795 or by siRNA-mediated knockdown abrogates HMPV-induced expression of IRF1. Moreover, we show that canonical NF-κB signaling is involved in IRF1 induction and that the TBK1/IKKε inhibitor BX795, but not siTBK1 treatment, impairs HMPV-induced phosphorylation of the NF-κB subunit p65. At later time-points of the infection, IRF1 expression depended heavily on IFN-ß-mediated signaling via the IFNAR-STAT1 pathway. Hence, our results suggest that TBK1 activation and TBK1/IKKε-mediated phosphorylation of the NF-κB subunit p65 control transcription of IRF1. Our study identifies a novel mechanism for IRF1 induction in response to viral infection of human macrophages that could be relevant not only to defense against HMPV, but also to other viral, bacterial and fungal pathogens.


Assuntos
Imunidade Inata , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/imunologia , Interferon Tipo I/imunologia , Metapneumovirus/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Linhagem Celular , Células Cultivadas , Humanos , Interferon Tipo I/genética , Metapneumovirus/genética , Monócitos/imunologia , Monócitos/virologia , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
10.
Sci Rep ; 11(1): 13638, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34211037

RESUMO

Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 and TNF. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19. We studied how cells detect SARS-CoV-2 infection. We report that the cytosolic RNA sensor MDA5 was required for type I and III IFN induction in the lung cancer cell line Calu-3 upon SARS-CoV-2 infection. Type I and III IFN induction further required MAVS and IRF3. In contrast, induction of IL6 and TNF was independent of the MDA5-MAVS-IRF3 axis in this setting. We further found that SARS-CoV-2 infection inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 as a cellular sensor for SARS-CoV-2 infection that induced type I and III IFNs.


Assuntos
COVID-19/imunologia , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Interferons/imunologia , SARS-CoV-2/imunologia , Linhagem Celular , Humanos , Imunidade Inata , RNA/imunologia
11.
Front Immunol ; 12: 685344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211472

RESUMO

Vaccination is the best prophylaxis for the prevention of infectious diseases, including coronavirus disease 2019. However, the efficacy of vaccines and onset of adverse reactions vary among individuals. Circulating extracellular vesicles (EVs) regulate the immune responses after vaccination by delivering microRNAs (miRNAs) to myeloid and lymphoid cells. Among these, miR-192 levels in serum EVs increase with aging, in an IL-6-dependent manner, reducing excessive IL-6 expression in aged mice, creating a negative feedback loop. Excessive IL-6 expression reduces vaccination efficacy in aged mice, while EV miR-192 improves efficacy in these aged mice as well, making this miRNA an interesting focus of study. miR-21 levels in serum EVs also increase with aging, and regulates the expression of IL-12 required for Th1 responses; therefore, EV miR-21 is expected to regulate vaccine efficacy. miR-451a, another important miRNA, is abundant in serum EVs and controls the expression of cytokines, such as type I interferon and IL-6. However, levels differ among individuals and correlate with local inflammatory symptoms experienced after a seasonal flu vaccination. These findings suggest the importance of EV miRNAs as a tool to improve vaccine efficacy and also as biomarkers to predict the immune response and adverse reactions after vaccinations.


Assuntos
Vesículas Extracelulares/metabolismo , Interferon Tipo I/imunologia , Interleucina-6/imunologia , MicroRNAs/sangue , Envelhecimento/sangue , Envelhecimento/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Interferon Tipo I/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Subunidade p35 da Interleucina-12/imunologia , Interleucina-6/biossíntese , MicroRNAs/genética , SARS-CoV-2/imunologia , Células Th1/imunologia , Vacinação
12.
Viruses ; 13(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202029

RESUMO

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency virus -1 (HIV-1), as a novel HIV-1 integrase inhibitor, and a strong anticancer immune response in an IFN-I-dependent manner, as a novel potential adjuvant in anticancer immunotherapy. Here, we report that Poly6 exerts an anti-SARS-CoV-2 effect, with an estimated 50% inhibitory concentration of 2.617 µM, in the human bronchial epithelial cell line, Calu-3 but not in Vero-E6 cells, which are deficient in type 1 interferon (IFN-I) signaling. We proved via assays based on mRNA profiles, inhibitors, or blocking antibodies that Poly6 can exert an anti-SARS-CoV-2 effect in an IFN-I-dependent manner. We also found that Poly6 inhibits IL-6 production enhanced by SARS-CoV-2 in infected Calu-3 cells at both the transcription and the translation levels, mediated via IL-10 induction in an IFN-I-dependent manner. These results indicate the feasibility of Poly6 as an IFN-I-inducing COVID-19 drug with potent antiviral and anti-inflammatory activities.


Assuntos
Antivirais/farmacologia , Células Epiteliais/efeitos dos fármacos , Vírus da Hepatite B/química , Interferon Tipo I/imunologia , Peptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Brônquios/citologia , Brônquios/virologia , Chlorocebus aethiops , Células Epiteliais/imunologia , Células Epiteliais/virologia , Vírus da Hepatite B/genética , Humanos , Pulmão/citologia , Pulmão/virologia , Peptídeos/imunologia , SARS-CoV-2/imunologia , Células Vero
13.
Nat Commun ; 12(1): 4175, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234126

RESUMO

Although we can now measure single-cell signaling responses with multivariate, high-throughput techniques our ability to interpret such measurements is still limited. Even interpretation of dose-response based on single-cell data is not straightforward: signaling responses can differ significantly between cells, encompass multiple signaling effectors, and have dynamic character. Here, we use probabilistic modeling and information-theory to introduce fractional response analysis (FRA), which quantifies changes in fractions of cells with given response levels. FRA can be universally performed for heterogeneous, multivariate, and dynamic measurements and, as we demonstrate, quantifies otherwise hidden patterns in single-cell data. In particular, we show that fractional responses to type I interferon in human peripheral blood mononuclear cells are very similar across different cell types, despite significant differences in mean or median responses and degrees of cell-to-cell heterogeneity. Further, we demonstrate that fractional responses to cytokines scale linearly with the log of the cytokine dose, which uncovers that heterogeneous cellular populations are sensitive to fold-changes in the dose, as opposed to additive changes.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/metabolismo , Modelos Imunológicos , Células 3T3 , Animais , Voluntários Saudáveis , Humanos , Interferon Tipo I/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Modelos Estatísticos , Cultura Primária de Células , Transdução de Sinais/imunologia , Análise de Célula Única , Software
14.
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
15.
Mol Cells ; 44(6): 384-391, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34098591

RESUMO

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/patogenicidade , Síndrome Respiratória Aguda Grave/imunologia , Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , COVID-19/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Dexametasona/uso terapêutico , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interleucinas/genética , Interleucinas/imunologia , SARS-CoV-2/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais , Análise de Sobrevida
16.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34108245

RESUMO

Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1ß, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.


Assuntos
Hipóxia Celular/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Monócitos/imunologia , COVID-19/imunologia , Células Cultivadas , Citocinas/imunologia , Humanos , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interleucina-1beta/metabolismo , Monócitos/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Oxigênio/metabolismo , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/metabolismo
17.
J Clin Invest ; 131(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34061776

RESUMO

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.


Assuntos
Autoanticorpos/imunologia , COVID-19/complicações , COVID-19/imunologia , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , SARS-CoV-2 , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Autoanticorpos/sangue , Feminino , Humanos , Técnicas In Vitro , Interferon-alfa/antagonistas & inibidores , Interferon-alfa/imunologia , Masculino , Poliendocrinopatias Autoimunes/genética , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Fatores de Transcrição/genética , Replicação Viral/imunologia , Adulto Jovem
18.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071130

RESUMO

The diagnosis of autoimmune polyglandular syndrome (APS) types 1/2 is difficult due to their rarity and nonspecific clinical manifestations. APS-1 development can be identified with assays for autoantibodies against cytokines, and APS-2 development with organ-specific antibodies. In this study, a microarray-based multiplex assay was proposed for simultaneous detection of both organ-specific (anti-21-OH, anti-GAD-65, anti-IA2, anti-ICA, anti-TG, and anti-TPO) and APS-1-specific (anti-IFN-ω, anti-IFN-α-2a, and anti-IL-22) autoantibodies. Herein, 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies or non-autoimmune endocrine pathologies and from healthy donors were analyzed. The prevalence of autoantibodies differed among the groups of healthy donors and patients with non-, mono- and multi-endocrine diseases. APS-1 patients were characterized by the presence of at least two specific autoantibodies (specificity 99.5%, sensitivity 100%). Furthermore, in 16 of the 18 patients, the APS-1 assay revealed triple positivity for autoantibodies against IFN-ω, IFN-α-2a and IL-22 (specificity 100%, sensitivity 88.9%). No anti-cytokine autoantibodies were found in the group of patients with non-APS-1 polyendocrine autoimmunity. The accuracy of the microarray-based assay compared to ELISA for organ-specific autoantibodies was 88.8-97.6%. This multiplex assay can be part of the strategy for diagnosing and predicting the development of APS.


Assuntos
Autoanticorpos/sangue , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Autoantígenos/imunologia , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/imunologia , Feminino , Humanos , Proteínas Imobilizadas/imunologia , Interferon Tipo I/imunologia , Interferon alfa-2/imunologia , Interleucinas/imunologia , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Especificidade de Órgãos , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/diagnóstico , Sensibilidade e Especificidade , Adulto Jovem
19.
Nat Immunol ; 22(7): 820-828, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33976430

RESUMO

Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity1,2. Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.


Assuntos
COVID-19/imunologia , Proteína DEAD-box 58/imunologia , Pulmão/imunologia , Receptores Imunológicos/imunologia , SARS-CoV-2/imunologia , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Cães , Células HEK293 , Humanos , Interferon Tipo I/imunologia , Interferons/imunologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Doença Pulmonar Obstrutiva Crônica/imunologia , RNA Polimerase Dependente de RNA/imunologia , Células Sf9 , Transdução de Sinais/imunologia , Células Vero , Proteínas Virais/imunologia
20.
Immunity ; 54(5): 856-858, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979584

RESUMO

Intestinal microbiome perturbation characterizes Crohn's disease (CD), though specific contributors to pathophysiology remain elusive. In a recent issue of Science, Jain et al. show that Debaryomyces hansenii impairs intestinal healing in mice via effects on type I interferon signaling and chemokine CCL5 expression in macrophages and that it is also prevalent in the inflamed mucosa of CD patients.


Assuntos
Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Mucosa Intestinal/microbiologia , Cicatrização/imunologia , Animais , Quimiocina CCL5/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Interferon Tipo I/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Camundongos , Micoses/imunologia , Micoses/microbiologia , Saccharomycetales/imunologia , Transdução de Sinais/imunologia
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