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1.
Nat Commun ; 10(1): 2887, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253760

RESUMO

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.


Assuntos
Candidíase/metabolismo , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Melioidose/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Animais , Burkholderia pseudomallei , Candida albicans , Candidíase/imunologia , Candidíase/microbiologia , Regulação da Expressão Gênica/imunologia , Vírus da Influenza A Subtipo H3N2 , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon gama/sangue , Interferon gama/genética , Pulmão , Melioidose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Receptor de Interferon alfa e beta , Receptores de Interferon , Infecções por Vírus Respiratório Sincicial/imunologia
2.
J Microbiol Biotechnol ; 29(7): 1137-1143, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216792

RESUMO

Hepatitis E virus (HEV) accounts for 20 million infections in humans worldwide. In most cases, the infections are self-limiting while HEV genotype 1 infection cases may lead to lethal infections in pregnant women (~ 20% fatality). The lack of small animal models has hampered detailed analysis of virus-host interactions and HEV-induced pathology. Here, by employing a recently developed culture-adapted HEV, we demonstrated that methyltransferase, a nonstructural protein, strongly inhibits melanoma differentiation-associated gene 5 (MDA5)- mediated activation of type I interferon responses. Compared to uninfected controls, HEVinfected cells display significantly lower levels of IFN-ß promoter activation when assessed by luciferase assay and RT-PCR. HEV genome-wide screening showed that HEV-encoded methyltransferase (MeT) strongly inhibits MDA5-mediated transcriptional activation of IFN-ß and NF-κB in a dose-responsive manner whether or not it is expressed in the presence/ absence of a tag fused to it. Taken together, current studies clearly demonstrated that HEV MeT is a novel antagonist of MDA5-mediated induction of IFN-ß signaling.


Assuntos
Vírus da Hepatite E/fisiologia , Hepatite E/metabolismo , Interferon Tipo I/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , Metiltransferases/metabolismo , Proteínas Virais/metabolismo , Células A549 , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Interferon Tipo I/genética , Interferon beta/genética , Interferon beta/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Transcrição Genética
3.
Nat Immunol ; 20(7): 915-927, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31110316

RESUMO

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.


Assuntos
Perfilação da Expressão Gênica , Interferon Tipo I/metabolismo , Queratinócitos/metabolismo , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Transcriptoma , Biópsia , Linhagem da Célula/genética , Biologia Computacional/métodos , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Perfilação da Expressão Gênica/métodos , Humanos , Nefrite Lúpica/patologia , Ligação Proteica , Transdução de Sinais , Análise de Célula Única , Pele/imunologia , Pele/metabolismo , Pele/patologia
4.
Nat Immunol ; 20(6): 701-710, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110314

RESUMO

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Caquexia/etiologia , Viroses/complicações , Viroses/imunologia , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia/diagnóstico por imagem , Caquexia/metabolismo , Caquexia/patologia , Doença Crônica , Citocinas/sangue , Citocinas/metabolismo , Feminino , Interferon Tipo I/metabolismo , Metabolismo dos Lipídeos , Lipólise , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Transdução de Sinais , Viroses/virologia
5.
Nat Commun ; 10(1): 2164, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092820

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/genética , Regiões 3' não Traduzidas/genética , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Genes Ligados ao Cromossomo X/imunologia , Predisposição Genética para Doença , Humanos , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Receptor 7 Toll-Like/genética
6.
Nat Commun ; 10(1): 2201, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101814

RESUMO

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Criança , Modelos Animais de Doenças , Feminino , Frequência do Gene , Células HEK293 , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma , Quinases da Família src/metabolismo
7.
Microb Pathog ; 132: 162-165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054871

RESUMO

Head and neck cancers (HNCs) are a major health problem and a leading cause of morbidity and mortality worldwide. More than 90% of these tumours are head and neck squamous cell carcinomas (HNSCCs). Amongst the common risk factors for HNCs (tobacco and alcohol use), there is a strong association of human papillomavirus (HPV) with HNSCCs. HPV type 16 (HPV 16), the major high-risk HPV type, is most commonly associated with HPV-driven HNSCCs. The promiscuous nature of the major HPV oncogene, E7, allows its interaction with a myriad of host proteins including STING, a component of the viral DNA-sensing cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) machinery. Sensing of viral DNA by the cGAS-STING machinery results in a type I interferon (IFN)-mediated anti-viral response. Amelioration of IFN responses resulting from the direct blockade of STING by E7 was first demonstrated in high-risk HPV type 18 (HPV 18) positive (+) cervical squamous cell carcinoma (CESC) cells. However, the role of E7 from HPV 16 (HPV 16E7) in antagonising cGAS-STING responses have not been investigated, let alone in the context of HNSCCs. Here, we show that HPV 16E7+, but not HPV 16E7 negative (-), HNSCC cells respond poorly to cGAS-STING activation stimulus. We further confirm that this inhibition occurred via the highly conserved LXCXE motif in 16E7. This finding contributes to the better understanding of role of high-risk HPV E7 in blocking cGAS-STING pathway, especially in the context of HNSCCs.


Assuntos
DNA Viral/isolamento & purificação , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16/genética , Nucleotidiltransferases/genética , Infecções por Papillomavirus/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Linhagem Celular Tumoral , DNA Viral/genética , Regulação Viral da Expressão Gênica , Neoplasias de Cabeça e Pescoço/complicações , Papillomavirus Humano 16/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações
8.
PLoS Pathog ; 15(4): e1007745, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009517

RESUMO

The mechanisms by which the gut luminal environment is disturbed by the immune system to foster pathogenic bacterial growth and survival remain incompletely understood. Here, we show that STAT2 dependent type I IFN signaling contributes to the inflammatory environment by disrupting hypoxia enabling the pathogenic S. Typhimurium to outgrow the microbiota. Stat2-/- mice infected with S. Typhimurium exhibited impaired type I IFN induced transcriptional responses in cecal tissue and reduced bacterial burden in the intestinal lumen compared to infected wild-type mice. Although inflammatory pathology was similar between wild-type and Stat2-/- mice, we observed decreased hypoxia in the gut tissue of Stat2-/- mice. Neutrophil numbers were similar in wild-type and Stat2-/- mice, yet Stat2-/- mice showed reduced levels of myeloperoxidase activity. In vitro, the neutrophils from Stat2-/- mice produced lower levels of superoxide anion upon stimulation with the bacterial ligand N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence of IFNα compared to neutrophils from wild-type mice, indicating that the neutrophils were less functional in Stat2-/- mice. Cytochrome bd-II oxidase-mediated respiration enhances S. Typhimurium fitness in wild-type mice, while in Stat2-/- deficiency, this respiratory pathway did not provide a fitness advantage. Furthermore, luminal expansion of S. Typhimurium in wild-type mice was blunted in Stat2-/- mice. Compared to wild-type mice which exhibited a significant perturbation in Bacteroidetes abundance, Stat2-/- mice exhibited significantly less perturbation and higher levels of Bacteroidetes upon S. Typhimurium infection. Our results highlight STAT2 dependent type I IFN mediated inflammation in the gut as a novel mechanism promoting luminal expansion of S. Typhimurium.


Assuntos
Disbiose/imunologia , Gastroenterite/imunologia , Inflamação/imunologia , Interferon Tipo I/imunologia , Fator de Transcrição STAT2/fisiologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Células Cultivadas , Disbiose/metabolismo , Disbiose/patologia , Feminino , Gastroenterite/metabolismo , Gastroenterite/microbiologia , Gastroenterite/patologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Interferon Tipo I/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Neutrófilos/patologia , Fator de Transcrição STAT1/fisiologia , Infecções por Salmonella/metabolismo , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia
9.
Virus Res ; 266: 25-33, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959069

RESUMO

African swine fever virus causes a haemorrhagic fever in domestic pigs and wild boar. The continuing spread in Africa, Europe and Asia threatens the global pig industry. The lack of a vaccine limits disease control. To underpin rational strategies for vaccine development improved knowledge is needed of how the virus interacts with and modulates the host's responses to infection. The virus long double-stranded DNA genome codes for more than 160 proteins of which many are non-essential for replication in cells but can have important roles in evading the host's defences. Here we review knowledge of the pathways targeted by ASFV and the mechanisms by which these are inhibited. The impact of deleting single or multiple ASFV genes on virus replication in cells and infection in pigs is summarised providing information on strategies for rational development of modified live vaccines.


Assuntos
Vírus da Febre Suína Africana/fisiologia , Febre Suína Africana/imunologia , Evasão da Resposta Imune , Proteínas Virais/imunologia , Febre Suína Africana/virologia , Animais , Apoptose , Mediadores da Inflamação/metabolismo , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Macrófagos/virologia , Suínos , Proteínas Virais/genética , Vacinas Virais/genética , Vacinas Virais/imunologia , Replicação Viral
10.
Mol Immunol ; 109: 126-133, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30928727

RESUMO

Members of the tripartite motif (TRIM) family as E3 ubiquitin ligases have been regarded as critical regulators of innate immunity and antiviral response. However, the role of TRIM7 is still elusive. Here, we provide evidence for the importance of TRIM7 in regulation of the TLR4-mediated innate response. In detail, we find that TRIM7 is highly expressed in antigen-presenting cells like macrophages. Knockdown of TRIM7 clearly inhibits the LPS-induced production of IFN-ß, TNF-α and IL-6 in macrophages. Conversely, forced expression of TRIM7 could exert an opposite effect on these pro-inflammatory cytokines. Further analysis indicates that such effect is mediated by the TLR4-associated signaling pathways including MAPKs, NF-κB and IRF3-involved pathways. Truncation of the E3 ligase domain on TRIM7 may reduce the production of pro-inflammatory cytokines, suggesting a critical role of this domain in the regulation of LPS-initiated innate response. Taken together, we report here that TRIM7 may facilitate the TLR4-mediated innate response via its E3 ligase domain in macrophages, which provides new insight into the mechanistic role of TRIM7 in innate immunity.


Assuntos
Proteínas de Transporte/metabolismo , Imunidade , Macrófagos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/genética , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interferon Tipo I/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/farmacologia , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 116(12): 5487-5492, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819897

RESUMO

The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its biochemical function is largely unknown. Here we identify HDAC11 as an efficient lysine defatty-acylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we hypothesized and later biochemically validated SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I IFN receptor ubiquitination and cell surface level. Correspondingly, HDAC11 depletion increased type I IFN signaling in both cell culture and mice. This study not only demonstrates that HDAC11 has an activity that is much more efficient than the corresponding deacetylase activity, but also expands the physiological functions of HDAC11 and protein lysine fatty acylation, which opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.


Assuntos
Glicina Hidroximetiltransferase/metabolismo , Histona Desacetilases/metabolismo , Hidroximetil e Formil Transferases/metabolismo , Interferon Tipo I/metabolismo , Transdução de Sinais , Acilação , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia
12.
Immunity ; 50(3): 591-599.e6, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893587

RESUMO

Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target.


Assuntos
DNA Viral/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Nucleicos/metabolismo , Ligação Proteica/imunologia
13.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901970

RESUMO

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.


Assuntos
Interferon Tipo I/metabolismo , Interferons/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Ativação Enzimática , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo
14.
Mol Cell ; 74(1): 19-31.e7, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30878284

RESUMO

Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Alternative MAVS cleavage sites were used to ensure the inactivation of this critical protein. Elevated type I IFNs were detected in caspase-3-deficient cells without any infection. Casp3-/- mice consistently showed increased resistance to viral infection and experimental autoimmune encephalomyelitis. Our results demonstrate that apoptotic caspases control innate immunity and maintain immune homeostasis against viral infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Caspases/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Nucleotidiltransferases/metabolismo , Viroses/enzimologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Caspase 2/genética , Caspase 2/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Caspases/genética , Feminino , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/genética , Masculino , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/genética , Vírus Sendai/imunologia , Vírus Sendai/patogenicidade , Transdução de Sinais , Células THP-1 , Vírus Vaccinia/imunologia , Vírus Vaccinia/patogenicidade , Viroses/genética , Viroses/imunologia , Viroses/virologia
15.
Nature ; 566(7742): 73-78, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728521

RESUMO

Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.


Assuntos
Senescência Celular/genética , Inflamação/genética , Interferon Tipo I/metabolismo , Elementos Nucleotídeos Longos e Dispersos/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Regulação para Baixo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Inflamação/patologia , Lamivudina/farmacologia , Masculino , Camundongos , Fenótipo , DNA Polimerase Dirigida por RNA/genética , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia
16.
Fish Shellfish Immunol ; 87: 721-729, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30753916

RESUMO

Salmonella is a facultative intracellular pathogen that can cause significant morbidity and mortality in humans and animals. Salmonella plasmid virulence (spv) gene sequence is a highly conserved 6.8 kb region which exists in the plasmid of most pathogenic Salmonella. Autophagy is a degradation process of unnecessary and dysfunctional cytoplasm components to maintain cellular homeostasis, which could affect host inflammatory responses, such as type I interferon response. Type I interferon response can promote the antibacterial activity of macrophage as well as the secretion of cytokines and neutrophil chemokines. We previously reported that spv locus could suppress autophagy and the aggregation of neutrophils in zebrafish larvae. To explore the influence of spv locus on Salmonella escaping from the innate immune responses and the underlying mechanism, the models of Salmonella enterica serovar Typhimurium infected macrophages in vitro and zebrafish larvae in vivo were used in this study. The interactions among spv locus, autophagy, type I interferon response and the chemotaxis of neutrophils were investigated. Western blot was used to detect the expression levels of autophagy related proteins and RT-qPCR was used to measure the mRNA levels of type I interferon response and the neutrophil chemokines. The chemotaxis of neutrophils were observed by Laser Scanning confocal microscopy. Autophagy agonist Torin 1 was also involved to interfere the autophagy influx. Results showed that spv locus could restrain type I interferon response and the chemotaxis of neutrophils via suppressing autophagy, which provided substantial foundation to study the mechanism of Salmonella escaping the innate immunity.


Assuntos
Autofagia , Imunidade Inata/fisiologia , Interferon Tipo I/metabolismo , Neutrófilos/imunologia , Salmonella typhimurium/fisiologia , Salmonella typhimurium/patogenicidade , Peixe-Zebra/fisiologia , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Quimiotaxia , Doenças dos Peixes/imunologia , Proteínas de Peixes/metabolismo , Plasmídeos/fisiologia , Distribuição Aleatória , Salmonelose Animal/imunologia , Virulência , Fatores de Virulência/genética , Fatores de Virulência/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia
17.
Int J Mol Sci ; 20(4)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791397

RESUMO

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4⁺ T cells' proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.


Assuntos
Células Dendríticas/imunologia , Fator Regulador 3 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Mycobacterium bovis , Nucleotidiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tuberculose Bovina/imunologia , Tuberculose Bovina/metabolismo , Animais , Bovinos , Diferenciação Celular , Células Dendríticas/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Camundongos , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tuberculose Bovina/microbiologia
18.
Immunity ; 50(1): 77-90.e5, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611612

RESUMO

Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. We found that conditional ablation of the Ets-family transcription factor PU.1 in DC-restricted progenitors led to increased pDC production at the expense of cDCs. PU.1 controlled many of the cardinal functions of DCs, such as antigen presentation by cDCs and type I interferon production by pDCs. Conditional ablation of PU.1 de-repressed the pDC transcriptional signature in cDCs. The combination of genome-wide mapping of PU.1 binding and gene expression analysis revealed a key role for PU.1 in maintaining cDC identity through the induction of the transcriptional regulator DC-SCRIPT. PU.1 activated DC-SCRIPT expression, which in turn promoted cDC formation, particularly of cDC1s, and repressed pDC development. Thus, cDC identity is regulated by a transcriptional node requiring PU.1 and DC-SCRIPT.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apresentação do Antígeno , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interferon Tipo I/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição/genética , Transcriptoma
19.
Immunity ; 50(1): 37-50, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650380

RESUMO

Plasmacytoid dendritic cells (pDCs) are a unique sentinel cell type that can detect pathogen-derived nucleic acids and respond with rapid and massive production of type I interferon. This review summarizes our current understanding of pDC biology, including transcriptional regulation, heterogeneity, role in antiviral immune responses, and involvement in immune pathology, particularly in autoimmune diseases, immunodeficiency, and cancer. We also highlight the remaining gaps in our knowledge and important questions for the field, such as the molecular basis of unique interferon-producing capacity of pDCs. A better understanding of cell type-specific positive and negative control of pDC function should pave the way for translational applications focused on this immune cell type.


Assuntos
Doenças Autoimunes/imunologia , Diferenciação Celular , Células Dendríticas/fisiologia , Neoplasias/imunologia , Viroses/imunologia , Animais , Regulação da Expressão Gênica , Humanos , Imunidade Celular , Interferon Tipo I/metabolismo
20.
Mol Cell ; 73(4): 803-814.e6, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30639243

RESUMO

Intron retention (IR) has emerged as an important mechanism of gene expression control, but the factors controlling IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified BUD13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in BUD13 was associated with increased IR, decreased mature Irf7 transcript and protein levels, and consequently a dampened type I interferon response, which compromised the ability of BUD13-deficient macrophages to withstand vesicular stomatitis virus (VSV) infection. Global analysis of BUD13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a BUD13-dependent manner. Deficiency of BUD13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, BUD13 facilitates the expression of genes at which IR occurs.


Assuntos
Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Íntrons , Macrófagos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Estomatite Vesicular/metabolismo , Vírus da Estomatite Vesicular Indiana/patogenicidade , Animais , Sítios de Ligação , Cercopithecus aethiops , Sequência Rica em GC , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Fator Regulador 7 de Interferon/genética , Interferon Tipo I/imunologia , Macrófagos/imunologia , Macrófagos/virologia , Camundongos Endogâmicos C57BL , Ligação Proteica , Sítios de Splice de RNA , Processamento de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Células Vero , Estomatite Vesicular/genética , Estomatite Vesicular/imunologia , Estomatite Vesicular/virologia , Vírus da Estomatite Vesicular Indiana/imunologia
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