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1.
Curr Opin Immunol ; 78: 102248, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36193584

RESUMO

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes (STING) and endoplasmic reticulum interferon stimulator (ERIS)) is an ER-associated protein that senses cellular and bacterium-derived cyclic dinucleotide (CDN), leading to induction of type-I interferons (IFNs) and innate immune responses against viruses and bacteria. Recently, it has become clear that sensing of CDN and induction of autophagy are two evolutionarily conserved functions of MITA, predating its role in mediating type-I IFN induction. Studies have shown that MITA-mediated signaling promotes a number of autoimmune disorders caused by gene mutations in human. Here, we summarize the most recent progress on MITA-mediated signaling in a view of evolution and highlight the roles of MITA in human inflammatory disorders caused by gene mutations and in genetically modified mouse models. We also briefly introduce the chemicals targeting MITA and discuss their potential in treatment of MITA-mediated inflammatory diseases. Finally, we propose several key questions that should be addressed for targeting MITA for treatment of related autoimmune diseases.


Assuntos
Doenças Autoimunes , Interferon Tipo I , Proteínas de Membrana , Animais , Humanos , Camundongos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade , Imunidade Inata , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Viroses/imunologia , Viroses/metabolismo
2.
Curr Opin Immunol ; 78: 102250, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36209576

RESUMO

Recent advances in our understanding of nucleic acid pattern-recognition receptor (PRR) sensing of viruses have revealed a previously unappreciated level of complexity of the host antiviral response. As well as direct recognition of viral nucleic acid by PRRs, viruses also induce the release of host nucleic acid from the nucleus and mitochondria into the cytosol, which boosts nucleic acid activation of antiviral PRRs. Crosstalk and cooperation between DNA- and RNA-recognition signaling pathways has also been revealed, as has direct restriction of viral genomes in an interferon-independent manner by PRRs, and new roles for inflammasomes in sensing viral nucleic acid. Further, newly identified viral-evasion strategies targeting PRR pathways emphasize the importance of nucleic acid detection during viral infection at the host-pathogen innate immune interface.


Assuntos
Imunidade Inata , Ácidos Nucleicos , Viroses , Humanos , Antivirais , Inflamassomos , Interferons , Ácidos Nucleicos/imunologia , Ácidos Nucleicos/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , RNA , Viroses/imunologia , Viroses/metabolismo , Vírus/imunologia
3.
Curr Opin Immunol ; 78: 102251, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36242870

RESUMO

The interferon-regulated kinase PKR (protein kinase RNA-activated) is a potent innate immune factor against a broad range of viruses. Being part of the integrated stress response (ISR), its restrictive effect is predominantly exerted by phosphorylating the eukaryotic translation-initiation factor eIF2, thereby turning it into an inhibitor of translation-initiation factor eIF2B. A plethora of viruses are known to evade the shutdown of cellular mRNA translation by interfering either with PKR activation or with eIF2 phosphorylation. Recently, a novel PKR evasion strategy was described: proteins from three taxonomically distinct RNA viruses allow for full PKR activation and eIF2 phosphorylation in the infected cell, but protect eIF2B from inhibition by phosphorylated eIF2, thus enabling mRNA translation in the presence of an activated ISR.


Assuntos
Fator de Iniciação 2B em Eucariotos , Fator de Iniciação 2 em Eucariotos , Imunidade Inata , Viroses , Humanos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Imunidade Inata/genética , Imunidade Inata/fisiologia , Interferons , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , RNA Mensageiro , Viroses/genética , Viroses/imunologia , Viroses/metabolismo
4.
J Virol ; 96(18): e0121222, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36069553

RESUMO

The mitochondrial apoptosis pathway has the function to kill the cell, but recent work shows that this pathway can also be activated to a sublethal level, where signal transduction can be observed but the cell survives. Intriguingly, this signaling has been shown to contribute to inflammatory activity of epithelial cells upon infection with numerous agents. This suggests that microbial recognition can generate sublethal activity in the mitochondrial apoptosis pathway. Because this recognition is achieved by pattern recognition receptors (PRRs), it also implies that PRR signals are linked to the mitochondrial apoptosis apparatus. We here test this hypothesis during infection of epithelial cells with modified vaccinia virus Ankara (MVA). MVA recognition is achieved through receptors specific for nucleic acids, and we present evidence that the three receptors, Toll-like receptor 3 (TLR3), RIG-I/MDA5, and cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING), are involved in this signaling. When stimulated directly by specific ligands, all three receptors could trigger sublethal apoptosis signals. During infection with MVA, sublethal apoptosis signals were unmasked in X-linked IAP (XIAP)-deficient cells, where apoptosis induction was observed. Deletion of any of the three signaling adapters, TRIF, MAVS, and STING, reduced the DNA damage response, a sensitive measure of sublethal apoptosis signals. Our results suggest that PRRs signal via mitochondria, where they generate sublethal signals through the BCL-2-family, which may contribute to the response to infectious agents. IMPORTANCE A contribution of the mitochondrial apoptosis apparatus, in the absence of cell death, to the reaction of nonprofessional immune cells to viruses is suggested to play a role as a broad alert system of an infected cell: the apoptosis system can be activated by many upstream signals and could therefore act as a central coordinator of viral recognition. The proapoptotic activity of PRRs has been documented in multiple situations, but this activity seems too low to be meaningful, and a physiological significance of such activity is not immediately obvious. This work suggests the alternative interpretation that PRRs do not have the primary function to induce apoptosis but to trigger sublethal signals in the apoptosis system. A number of lines of recent research suggest that mitochondria contribute to cellular reactions, and this pathway may be a way of triggering an early host response.


Assuntos
Apoptose , Mitocôndrias , Ácidos Nucleicos , Receptores de Reconhecimento de Padrão , Viroses , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Humanos , Imunidade Inata , Mitocôndrias/imunologia , Nucleotidiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptor 3 Toll-Like/metabolismo , Vírus Vaccinia , Viroses/imunologia
5.
Front Immunol ; 13: 942465, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36045674

RESUMO

Follicular helper T (TFH) cells provide specialized help for B cells to ensure optimal humoral immunity. The histone methyltransferase EZH2, as a chromatin repressor, secures the TFH differentiation by promoting TFH lineage associated gene expression during acute viral infection, including Tcf7 and Bcl6. By using conditional deletion murine system, we observed that EZH2 ablation in CD4+ T cells was accompanied by aberrant accumulation of DNA methyltransferases (DNMTs) DNMT1 and DNMT3B in TFH cells. And the loss of EZH2 promoted aggravation of DNA methylation status at Tcf7 locus. Therefore, our findings suggested that EZH2 plays an important role in maintenance of hypomethylation at Tcf7 locus thus affecting TFH differentiation during acute viral infection.


Assuntos
Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Linfócitos T Auxiliares-Indutores , Viroses , Animais , Diferenciação Celular , Histona Metiltransferases/metabolismo , Camundongos , Viroses/imunologia
6.
Cells ; 11(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36078113

RESUMO

The innate immune system is the first line of defense against bacterial and viral infections and sterile inflammation through the recognition of pathogen-associated molecular patterns (PAMPs) as well as danger-associated molecular patterns (DAMPs) by pathogen-recognition receptors (PRRs), and produces proinflammatory and antiviral cytokines and chemokines [...].


Assuntos
Imunidade Inata , Alarminas , Infecções Bacterianas/imunologia , Citocinas , Humanos , Receptores de Reconhecimento de Padrão , Viroses/imunologia
7.
J Gen Virol ; 103(8)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36006669

RESUMO

DExH/D-box helicases are essential nucleic acid and ribonucleoprotein remodelers involved in all aspects of nucleic acid metabolism including replication, gene expression and post-transcriptional modifications. In parallel to their importance in basic cellular functions, DExH/D-box helicases play multiple roles in viral life cycles, with some of them highjacked by viruses or negatively regulating innate immune activation. However, other DExH/D-box helicases have recurrently been highlighted as direct antiviral effectors or as positive regulators of innate immune activation. Innate immunity relies on the ability of Pathogen Recognition Receptors to recognize viral signatures and trigger the production of interferons (IFNs) and pro-inflammatory cytokines. Secreted IFNs interact with their receptors to establish antiviral cellular reprogramming via expression regulation of the interferon-stimulated genes (ISGs). Several DExH/D-box helicases have been reported to act as viral sensors (DDX3, DDX41, DHX9, DDX1/DDX21/DHX36 complex), and others to play roles in innate immune activation (DDX60, DDX60L, DDX23). In contrast, the DDX39A, DDX46, DDX5 and DDX24 helicases act as negative regulators and impede IFN production upon viral infection. Beyond their role in viral sensing, the ISGs DDX60 and DDX60L act as viral inhibitors. Interestingly, the constitutively expressed DEAD-box helicases DDX56, DDX17, DDX42 intrinsically restrict viral replication. Hence, DExH/D-box helicases appear to form a multilayer network of primary and secondary factors involved in both intrinsic and innate antiviral immunity. In this review, we highlight recent findings on the extent of antiviral defences played by helicases and emphasize the need to better understand their immune functions as well as their complex interplay.


Assuntos
RNA Helicases DEAD-box/metabolismo , Imunidade Inata , Viroses , RNA Helicases DEAD-box/genética , DNA Helicases , Humanos , Ácidos Nucleicos , Ribonucleoproteína Nuclear Pequena U2 , Viroses/imunologia , Viroses/metabolismo
8.
Proc Natl Acad Sci U S A ; 119(33): e2204235119, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35939694

RESUMO

Mammalian cells respond to dsRNA in multiple manners. One key response to dsRNA is the activation of PKR, an eIF2α kinase, which triggers translational arrest and the formation of stress granules. However, the process of PKR activation in cells is not fully understood. In response to increased endogenous or exogenous dsRNA, we observed that PKR forms novel cytosolic condensates, referred to as dsRNA-induced foci (dRIFs). dRIFs contain dsRNA, form in proportion to dsRNA, and are enhanced by longer dsRNAs. dRIFs enrich several other dsRNA-binding proteins, including ADAR1, Stau1, NLRP1, and PACT. Strikingly, dRIFs correlate with and form before translation repression by PKR and localize to regions of cells where PKR activation is initiated. We hypothesize that dRIF formation is a mechanism that cells use to enhance the sensitivity of PKR activation in response to low levels of dsRNA or to overcome viral inhibitors of PKR activation.


Assuntos
RNA de Cadeia Dupla , RNA Viral , Viroses , eIF-2 Quinase , Ativação Enzimática , Humanos , Imunidade Inata , Fosforilação , Biossíntese de Proteínas , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/imunologia , RNA Viral/química , RNA Viral/imunologia , Proteínas de Ligação a RNA/química , Grânulos de Estresse , Viroses/enzimologia , Viroses/imunologia , eIF-2 Quinase/química
9.
Nature ; 608(7924): 757-765, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35948641

RESUMO

The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago1,2. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4. The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5-8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8-14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR-Cas9-mediated deletion of a transposable element-namely the LINE-1 retrotransposon Lx9c11-in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11-/- mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.


Assuntos
Elementos de DNA Transponíveis , Interações entre Hospedeiro e Microrganismos , Imunidade , Retroelementos , Viroses , Animais , Sistemas CRISPR-Cas/genética , Elementos de DNA Transponíveis/genética , Elementos de DNA Transponíveis/imunologia , Evolução Molecular , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade/genética , Camundongos , RNA não Traduzido/genética , Sequências Reguladoras de Ácido Nucleico/genética , Retroelementos/genética , Retroelementos/imunologia , Viroses/genética , Viroses/imunologia
11.
Sci Immunol ; 7(73): eabm7996, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35857581

RESUMO

The acute effects of various respiratory viral infections have been well studied, with extensive characterization of the clinical presentation as well as viral pathogenesis and host responses. However, over the course of the recent COVID-19 pandemic, the incidence and prevalence of chronic sequelae after acute viral infections have become increasingly appreciated as a serious health concern. Post-acute sequelae of COVID-19, alternatively described as "long COVID-19," are characterized by symptoms that persist for longer than 28 days after recovery from acute illness. Although there exists substantial heterogeneity in the nature of the observed sequelae, this phenomenon has also been observed in the context of other respiratory viral infections including influenza virus, respiratory syncytial virus, rhinovirus, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome coronavirus. In this Review, we discuss the various sequelae observed following important human respiratory viral pathogens and our current understanding of the immunological mechanisms underlying the failure of restoration of homeostasis in the lung.


Assuntos
COVID-19 , Infecções Respiratórias , Viroses , COVID-19/complicações , COVID-19/imunologia , Coronavirus , Humanos , Pandemias , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Viroses/complicações , Viroses/imunologia
12.
Biochem Pharmacol ; 200: 115026, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35367198

RESUMO

The interferon regulatory factor (IRF) family of transcription factors play a vital role in the human innate antiviral immune responses with production of interferons (IFNs) as a hallmark outcome of activation. In recent years, IRF3 has been considered a principal early regulator of type I IFNs (TI-IFNs) directly downstream of intracellular virus sensing. Despite decades of research on IRF-activating pathways, many questions remain on the regulation of IRF3 activation. The kinases IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1) and the scaffold proteins TRAF family member-associated NF-kappa-B activator (TANK), NF-kappa-B-activating kinase-associated protein 1 (NAP1) and TANK-binding kinase 1-binding protein 1 (TBKBP1)/similar to NAP1 TBK1 adaptor (SINTBAD) are believed to be core components of an IRF3-activation complex yet their contextual involvement and complex composition are still unclear. This review will give an overview of antiviral signaling pathways leading to the activation of IRF3 and discuss recent developments in our understanding of its proximal regulation.


Assuntos
Imunidade Inata , Fator Regulador 3 de Interferon , Viroses , Humanos , Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Fosforilação , Transdução de Sinais , Viroses/imunologia
13.
Immunol Cell Biol ; 100(7): 529-546, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35471730

RESUMO

To control infections phagocytes can directly kill invading microbes. Macrophage-expressed gene 1 (Mpeg1), a pore-forming protein sometimes known as perforin-2, is reported to be essential for bacterial killing following phagocytosis. Mice homozygous for the mutant allele Mpeg1tm1Pod succumb to bacterial infection and exhibit deficiencies in bacterial killing in vitro. Here we describe a new Mpeg mutant allele Mpeg1tm1.1Pib on the C57BL/6J background. Mice homozygous for the new allele are not abnormally susceptible to bacterial or viral infection, and irrespective of genetic background show no perturbation in bacterial killing in vitro. Potential reasons for these conflicting findings are discussed. In further work, we show that cytokine responses to inflammatory mediators, as well as antibody generation, are also normal in Mpeg1tm1.1Pib/tm1.1Pib mice. We also show that Mpeg1 is localized to a CD68-positive endolysosomal compartment, and that it exists predominantly as a processed, two-chain disulfide-linked molecule. It is abundant in conventional dendritic cells 1, and mice lacking Mpeg1 do not present the model antigen ovalbumin efficiently. We conclude that Mpeg1 is not essential for innate antibacterial protection or antiviral immunity, but may play a focused role early in the adaptive immune response.


Assuntos
Apresentação de Antígeno , Proteínas Citotóxicas Formadoras de Poros , Animais , Infecções Bacterianas/imunologia , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Citotóxicas Formadoras de Poros/imunologia , Viroses/imunologia
14.
Clin Exp Immunol ; 209(1): 72-82, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35467728

RESUMO

Eosinophils are innate immune cells typically associated with allergic and parasitic diseases. However, in recent years, eosinophils have also been ascribed a role in keeping homeostasis and in fighting several infectious diseases. Indeed, these cells circulate as mature cells in the blood and can be quickly recruited to the infected tissue. Moreover, eosinophils have all the necessary cellular equipment such as pattern recognition receptors (PRRs), pro-inflammatory cytokines, anti-bacterial proteins, and DNA traps to fight pathogens and promote an efficient immune response. This review summarizes some of the updated information on the role of eosinophils' direct and indirect mediated interactions with pathogens.


Assuntos
Infecções Bacterianas , Eosinófilos , Micoses , Viroses , Infecções Bacterianas/imunologia , Citocinas/metabolismo , Eosinófilos/imunologia , Humanos , Imunidade Inata , Micoses/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Viroses/imunologia
15.
J Virol ; 96(7): e0020722, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35297670

RESUMO

Long noncoding RNAs (lncRNAs) widely exist in the cells and play important roles in various biological processes. The role of lncRNAs in immunity remains largely unknown. lncRNA BST2-2 (lncBST2-2) was upregulated upon viral infection and dependent on the interferon (IFN)/JAK/STAT signaling pathway. There was no coding potential found in the lncBST2-2 transcript. Overexpression of lncBST2-2 inhibited the replication of hepatitis C virus (HCV), Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), and herpes simplex virus (HSV), while knockdown of lncBST2-2 facilitated viral replication. Further studies showed that lncBST2-2 promoted the phosphorylation, dimerization, and nuclear transport of IRF3, promoting the production of IFNs. Importantly, lncBST2-2 interacted with the DNA-binding domain of IRF3, which augmented TBK1 and IRF3 interaction, thereby inducing robust production of IFNs. Moreover, lncBST2-2 impaired the interaction between IRF3 and PP2A-RACK1 complex, an essential step for the dephosphorylation of IRF3. These data shown that lncBST2-2 promotes the innate immune response to viral infection through targeting IRF3. Our study reveals the lncRNA involved in the activation of IRF3 and provides a new insight into the role of lncRNA in antiviral innate immunity. IMPORTANCE Innate immunity is an important part of the human immune system to resist the invasion of foreign pathogens. IRF3 plays a critical role in the innate immune response to viral infection. In this study, we demonstrated that lncBST2-2 plays an important role in innate immunity. Virus-induced lncBST2-2 positively regulates innate immunity by interacting with IRF3 and blocking the dephosphorylation effect of RACK1-PP2A complex on IRF3, thus inhibiting viral infection. Our study provides a new insight into the role of lncBST2-2 in the regulation of IRF3 signaling activation.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Inata , RNA Longo não Codificante , Viroses , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/genética , Fator Regulador 3 de Interferon/metabolismo , Interferons/metabolismo , RNA Longo não Codificante/genética , Viroses/genética , Viroses/imunologia , Replicação Viral , Vírus/imunologia
16.
J Virol ; 96(7): e0000122, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35254105

RESUMO

The induction of interferons (IFNs) plays an important role in the elimination of invading pathogens. Heat shock binding protein 21 (HBP21), first known as a molecular chaperone of HSP70, is involved in tumor development. Heat shock binding proteins have been shown to regulate diverse biological processes, such as cell cycle, kinetochore localization, transcription, and cilium formation. Their role in antimicrobial immunity remains unknown. Here, we found that HBP21 drives a positive feedback loop to promote IRF3-mediated IFN production triggered by viral infection. HBP21 deficiency significantly impaired the virus-induced production of IFN and resulted in greater susceptibility to viral infection both in vitro and in vivo. Mechanistically, HBP21 interacted with IRF3 and promoted the formation of a TBK1-IRF3 complex. Moreover, HBP21 abolished the interaction between PP2A and IRF3 to repress the dephosphorylation of IRF3. Analysis of HBP21 protein structure further confirmed that HBP21 promotes the activation of IRF3 by depressing the dephosphorylation of IRF3 by PP2A. Further study demonstrated that virus-induced phosphorylation of Ser85 and Ser153 of HBP21 itself is important for the phosphorylation and dimerization of IRF3. Our study identifies HBP21 as a new positive regulator of innate antiviral response, which adds novel insight into activation of IRF3 controlled by multiple networks that specify behavior of tumors and immunity. IMPORTANCE The innate immune system is the first-line host defense against microbial pathogen invasion. The physiological functions of molecular chaperones, involving cell differentiation, migration, proliferation and inflammation, have been intensively studied. HBP21 as a molecular chaperone is critical for tumor development. Tumor is related to immunity. Whether HBP21 regulates immunity remains unknown. Here, we found that HBP21 promotes innate immunity response by dual regulation of IRF3. HBP21 interacts with IRF3 and promotes the formation of a TBK1-IRF3 complex. Moreover, HBP21 disturbs the interaction between PP2A and IRF3 to depress the dephosphorylation of IRF3. Analysis of HBP21 protein structure confirms that HBP21 promotes the activation of IRF3 by blocking the dephosphorylation of IRF3 by PP2A. Interestingly, virus-induced Ser85 and Ser153 phosphorylation of HBP21 is important for IRF3 activation. Our findings add to the known novel immunological functions of molecular chaperones and provide new insights into the regulation of innate immunity.


Assuntos
Imunidade Inata , Chaperonas Moleculares , Viroses , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Fator Regulador 3 de Interferon/metabolismo , Chaperonas Moleculares/metabolismo , Fosforilação , Viroses/imunologia
17.
Sci Rep ; 12(1): 2582, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173190

RESUMO

There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.


Assuntos
Infecções Bacterianas/epidemiologia , Genes MHC da Classe II , Genes MHC Classe I , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Viroses/epidemiologia , Adulto , Idoso , Bactérias/isolamento & purificação , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Viroses/genética , Viroses/imunologia , Viroses/patologia , Vírus/isolamento & purificação
18.
J Virol ; 96(6): e0217521, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35107381

RESUMO

REC8 meiotic recombination protein (REC8) is a member of structural maintenance of chromosome (SMC) protein partners, which play an important role in meiosis, antitumor activity, and sperm formation. As the adaptor proteins of RIG-I-like receptor (RLR) signaling and cyclic GMP-AMP synthase (cGAS)-DNA signaling, the activity and stability of MAVS (mitochondrial antiviral signaling protein; also known as VISA, Cardif, and IPS-1) and STING (stimulator of interferon genes; also known as MITA) are critical for innate immunity. Here, we report that REC8 interacts with MAVS and STING and inhibits their ubiquitination and subsequent degradation, thereby promoting innate antiviral signaling. REC8 is upregulated through the JAK-STAT signaling pathway during viral infection. Knockdown of REC8 impairs the innate immune responses against vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and herpes simplex virus (HSV). Mechanistically, during infection with viruses, the SUMOylated REC8 is transferred from the nucleus to the cytoplasm and then interacts with MAVS and STING to inhibit their K48-linked ubiquitination triggered by RNF5. Moreover, REC8 promotes the recruitment of TBK1 to MAVS and STING. Thus, REC8 functions as a positive modulator of innate immunity. Our work highlights a previously undocumented role of meiosis-associated protein REC8 in regulating innate immunity. IMPORTANCE The innate immune response is crucial for the host to resist the invasion of viruses and other pathogens. STING and MAVS play a critical role in the innate immune response to DNA and RNA viral infection, respectively. In this study, REC8 promoted the innate immune response by targeting STING and MAVS. Notably, REC8 interacts with MAVS and STING in the cytoplasm and inhibits K48-linked ubiquitination of MAVS and STING triggered by RNF5, stabilizing MAVS and STING protein to promote innate immunity and gradually inhibiting viral infection. Our study provides a new insight for the study of antiviral innate immunity.


Assuntos
Proteínas de Ciclo Celular , Imunidade Inata , Viroses , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antivirais , Proteínas de Ciclo Celular/imunologia , Proteínas de Membrana/metabolismo , Vírus da Doença de Newcastle , Simplexvirus , Ubiquitinação , Vírus da Estomatite Vesicular Indiana , Viroses/imunologia
20.
Int J Mol Sci ; 23(4)2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35216425

RESUMO

Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial-viral-gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial-viral co-infection at the host intestinal immune interface from multiple perspectives.


Assuntos
Infecções Bacterianas/imunologia , Coinfecção/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Viroses/imunologia , Animais , Coinfecção/microbiologia , Coinfecção/virologia , Humanos , Mucosa Intestinal/virologia
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