Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.230
Filtrar
1.
Curr Opin Immunol ; 87: 102430, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38824869

RESUMO

Lambda interferons (IFNλs), also termed type III interferons (IFNs) or interleukins-28/29, have been in the shadow of type I IFNs for a long time. Their common induction mechanisms and signalling cascades with type I IFNs have made difficult the unwinding of their unique nonredundant functions. However, this is now changing with mounting evidence supporting a major role of IFNλs as a specialized antiviral defense system in the body, mediating protection at mucosal barrier surfaces while limiting immunopathology. Here, we review the latest progress on the complex activities of IFNλs in the respiratory tract, focusing on their multiple effects in IFNλ receptor-expressing cells, the modulation of innate and adaptive immune responses in the context of infections and respiratory diseases, and their similarities and differences with type I IFNs. We also discuss their potential in therapeutic applications and the most recent developments in that direction.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon lambda , Interferons , Sistema Respiratório , Humanos , Animais , Interferons/metabolismo , Interferons/imunologia , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismo , Transdução de Sinais/imunologia , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia
2.
Nat Commun ; 15(1): 4920, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858353

RESUMO

The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.


Assuntos
Epigênese Genética , Histona-Lisina N-Metiltransferase , Células Estromais , Útero , Feminino , Animais , Útero/metabolismo , Células Estromais/metabolismo , Camundongos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Interferons/metabolismo , Interferons/genética , Retrovirus Endógenos/genética , Apoptose/genética , Camundongos Endogâmicos C57BL , Morte Celular/genética , Necroptose/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Histonas/metabolismo , Análise de Célula Única , Camundongos Knockout , Diferenciação Celular/genética
4.
Cell Death Dis ; 15(5): 369, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38806478

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.


Assuntos
Leucemia Mieloide Aguda , Fator de Transcrição STAT3 , Animais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Humanos , Fator de Transcrição STAT3/metabolismo , Camundongos , Transdução de Sinais , Interferons/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/metabolismo , Receptor de Interferon alfa e beta/genética , Linhagem Celular Tumoral , Nitrilas , Pirazóis , Pirimidinas
5.
Eur J Med Chem ; 272: 116494, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38749268

RESUMO

Epigenetic alterations promote cancer development by regulating the expression of various oncogenes and anti-oncogenes. Histone methylation modification represents a pivotal area in epigenetic research and numerous publications have demonstrated that aberrant histone methylation is highly correlated with tumorigenesis and development. As a key histone demethylase, lysine-specific demethylase 5B (KDM5B) demethylates lysine 4 of histone 3 (H3K4) and serves as a transcriptional repressor of certain tumor suppressor genes. Meanwhile, KDM5B inhibits STING-induced intrinsic immune response of tumor cells or recruits SETDB1 through non-enzymatic function to silence reverse transcription elements to promote immune escape. The conventional small molecule inhibitors can only inhibit the enzymatic function of KDM5B with no effect on the non-enzymatic function. In the article, we present the development of the first series of KDM5B degraders based on CPI-455 to inhibit the non-enzymatic function. Among them, GT-653 showed optimal KDM5B degradation efficiency in a ubiquitin proteasome-dependent manner. GT-653 efficiently reduced KDM5B protein levels without affecting KDM5B transcription. Interestingly, GT-653 increased H3K4me3 levels and activated the type-I interferon signaling pathway in 22RV1 cells without significant phenotypic response on cell proliferation.


Assuntos
Antineoplásicos , Histona Desmetilases com o Domínio Jumonji , Neoplasias da Próstata , Humanos , Masculino , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Regulação para Cima/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Descoberta de Drogas , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Proteólise/efeitos dos fármacos , Interferons/metabolismo , Proteínas Nucleares , Proteínas Repressoras
6.
Proc Natl Acad Sci U S A ; 121(21): e2402540121, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38758698

RESUMO

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at an air-liquid interface (ALI). HCoV-229E, HCoV-NL63, and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33 °C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally directed IFNs as potential therapeutics.


Assuntos
Resfriado Comum , Imunidade Inata , Interferons , Mucosa Nasal , SARS-CoV-2 , Transdução de Sinais , Humanos , Mucosa Nasal/virologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Interferons/metabolismo , Interferons/imunologia , Resfriado Comum/imunologia , Resfriado Comum/virologia , Transdução de Sinais/imunologia , SARS-CoV-2/imunologia , Replicação Viral , Rhinovirus/imunologia , Coronavirus Humano 229E/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células Epiteliais/virologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavirus Humano NL63/imunologia
7.
Front Immunol ; 15: 1374368, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715616

RESUMO

NOD1 and NOD2 as two representative members of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family play important roles in antimicrobial immunity. However, transcription mechanism of nod1 and nod2 and their signal circle are less understood in teleost fish. In this study, with the cloning of card9 and ripk2 in Chinese perch, the interaction between NOD1, NOD2, and CARD9 and RIPK2 were revealed through coimmunoprecipitation and immunofluorescence assays. The overexpression of NOD1, NOD2, RIPK2 and CARD9 induced significantly the promoter activity of NF-κB, IFNh and IFNc. Furthermore, it was found that nod1 and nod2 were induced by poly(I:C), type I IFNs, RLR and even NOD1/NOD2 themselves through the ISRE site of their proximal promoters. It is thus indicated that nod1 and nod2 can be classified also as ISGs due to the presence of ISRE in their proximal promoter, and their expression can be mechanistically controlled through PRR pathway as well as through IFN signaling in antiviral immune response.


Assuntos
Proteínas de Peixes , Proteína Adaptadora de Sinalização NOD1 , Proteína Adaptadora de Sinalização NOD2 , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Transdução de Sinais , Animais , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Peixes/imunologia , Percas/genética , Percas/imunologia , Percas/metabolismo , Interferons/metabolismo , Interferons/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Imunidade Inata/genética , Ligação Proteica
8.
Cell Rep Med ; 5(5): 101569, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38744279

RESUMO

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8+GZMH+ cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.


Assuntos
Interferons , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Interferons/metabolismo , Interferons/genética , Feminino , Adulto , Masculino , Transcriptoma/genética , Interferon Tipo I/metabolismo , Interferon Tipo I/genética , Pessoa de Meia-Idade , Transcrição Gênica , Regulação da Expressão Gênica
9.
Genes (Basel) ; 15(5)2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38790257

RESUMO

BACKGROUND: Sjögren's disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by lymphocytes and the activation of B lymphocytes with the production of autoantibodies. We aimed to analyze the transcriptome of circulating B cells from patients with SJD and healthy controls to decipher the B-cell-specific contribution to SJD. METHODS: RNA from peripheral blood B cells of five untreated female patients with SjD and positive ANA, positive anti-SSA (both Ro-52 and Ro-60), positive anti-SSB and positive rheumatoid-factor, and five healthy controls was subjected to whole-transcriptome sequencing. A false discovery rate of < 0.1 was applied to define differentially expressed genes (DEG). RESULTS: RNA-sequencing identified 56 up and 23 down DEG. Hierarchal clustering showed a clear separation between the two groups. Ingenuity pathway analysis revealed that these genes may play a role in interferon signaling, chronic mycobacterial infection, and transformation to myeloproliferative disorders. CONCLUSIONS: We found upregulated expression of type-I and type-II interferon (IFN)-induced genes, as well as genes that may contribute to other concomitant conditions, including infections and a higher risk of myeloproliferative disorders. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies.


Assuntos
Linfócitos B , Perfilação da Expressão Gênica , Síndrome de Sjogren , Transcriptoma , Humanos , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Feminino , Linfócitos B/imunologia , Linfócitos B/metabolismo , Pessoa de Meia-Idade , Perfilação da Expressão Gênica/métodos , Interferons/genética , Interferons/metabolismo , Adulto , Autoanticorpos/imunologia , Autoanticorpos/sangue , Autoanticorpos/genética , Idoso
10.
Front Immunol ; 15: 1385473, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720890

RESUMO

Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggesting that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. To address this question, we conducted a comparative analysis of the transcriptomic profiles of human monocyte-derived macrophages (MDMs) exposed to IL-27 and those exposed to recombinant human IFN-α, IFN-γ, and IFN-λ. We utilized bioinformatics approaches to identify common differentially expressed genes between the different transcriptomes. To verify the accuracy of this approach, we used RT-qPCR, ELISA, flow cytometry, and microarrays data. We found that IFNs and IL-27 induce transcriptional changes in several genes, including those involved in JAK-STAT signaling, and induce shared pro-inflammatory and antiviral pathways in MDMs, leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs)Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response. Given this similarity, we propose that IL-27 could be classified as a distinct type of IFN, possibly categorized as IFN-pi (IFN-π), the type V IFN (IFN-V).


Assuntos
Febre de Chikungunya , Dengue , Interleucina-27 , Janus Quinases , Macrófagos , Transdução de Sinais , Humanos , Células Cultivadas , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/fisiologia , Vírus da Dengue/imunologia , Interferons/metabolismo , Interleucina-27/metabolismo , Interleucinas/imunologia , Interleucinas/farmacologia , Janus Quinases/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Transdução de Sinais/genética , Fatores de Transcrição STAT/metabolismo , Transcriptoma , Replicação Viral
11.
J Immunol ; 212(12): 1945-1957, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700419

RESUMO

The cytosolic detection of pathogen-derived nucleic acids has evolved as an essential strategy for host innate immune defense in mammals. One crucial component in this process is the stimulator of IFN genes (STING), which acts as a vital signaling adaptor, connecting the cytosolic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) to the downstream type I IFN signaling pathway. However, this process remains elusive in invertebrates. In this study, we present evidence demonstrating that STING, an ortholog found in a marine invertebrate (shrimp) called Litopenaeus vannamei, can directly detect DNA and initiate an IFN-like antiviral response. Unlike its homologs in other eukaryotic organisms, which exclusively function as sensors for cyclic dinucleotides, shrimp STING has the ability to bind to both double-stranded DNA and cyclic dinucleotides, including 2'3'-cGAMP. In vivo, shrimp STING can directly sense DNA nucleic acids from an infected virus, accelerate IFN regulatory factor dimerization and nuclear translocation, induce the expression of an IFN functional analog protein (Vago4), and finally establish an antiviral state. Taken together, our findings unveil a novel double-stranded DNA-STING-IKKε-IRF-Vago antiviral axis in an arthropod, providing valuable insights into the functional origins of DNA-sensing pathways in evolution.


Assuntos
Proteínas de Membrana , Animais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Penaeidae/imunologia , Penaeidae/virologia , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Interferons/metabolismo , Interferons/imunologia , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/imunologia
12.
Fish Shellfish Immunol ; 150: 109611, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38734119

RESUMO

During virus-host co-evolution, viruses have developed multiple strategies to dampen IFN response and prevent its antiviral activity in host cells. To date, the interactions between host IFN response and the immune evasion strategies exploited by fish iridoviruses still remain largely uncertain. Here, a potential immune evasion protein candidate of Singapore grouper iridovirus (SGIV), VP82 (encoded by SGIV ORF82) was screened and its roles during viral replication were investigated in detail. Firstly, VP82 overexpression dramatically decreased IFN or ISRE promoter activity and the transcription levels of IFN stimulated genes (ISGs) stimulated by grouper cyclic GMP-AMP synthase (EccGAS)/stimulator of interferon genes (EcSTING), TANK-binding kinase 1 (EcTBK1), IFN regulatory factor 3 (EcIRF3)and EcIRF7. Secondly, Co-IP assays indicated that VP82 interacted with EcIRF3 and EcIRF7, but not EcSTING and EcTBK1, which was consistent with the co-localization between VP82 and EcIRF3 or EcIRF7. Furthermore, VP82 promoted the degradation of EcIRF3 and EcIRF7 in a dose-dependent manner via the autophagy pathway. Finally, VP82 overexpression accelerated SGIV replication, evidenced by the increased transcriptions of viral core genes and viral production. Moreover, the antiviral action of EcIRF3 or EcIRF7 was significantly depressed in VP82 overexpressed cells. Together, VP82 was speculated to exert crucial roles for SGIV replication by inhibiting the IFN response via the degradation of IRF3 and IRF7. Our findings provided new insights into understanding the immune evasion strategies utilized by fish iridovirus through IFN regulation.


Assuntos
Infecções por Vírus de DNA , Doenças dos Peixes , Proteínas de Peixes , Fator Regulador 3 de Interferon , Fator Regulador 7 de Interferon , Ranavirus , Proteínas Virais , Animais , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Fator Regulador 7 de Interferon/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/metabolismo , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/veterinária , Ranavirus/fisiologia , Proteínas Virais/genética , Proteínas Virais/metabolismo , Imunidade Inata/genética , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Evasão da Resposta Imune , Bass/imunologia , Bass/genética , Replicação Viral , Proteínas de Peixe-Zebra , Fatores Reguladores de Interferon
13.
Curr Opin Immunol ; 87: 102425, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38763032

RESUMO

Interferons (IFNs) are an integral component of the host innate immune response during viral infection. Recent advances in the study of type I and III IFNs suggest that though both types counteract viral infection, type III IFNs act predominantly at epithelial barrier sites, while type I IFNs drive systemic responses. The dynamics and specific roles of type I versus III IFNs have been studied in the context of infection by a variety of enteric pathogens, including reovirus, rotavirus, norovirus, astrovirus, and intestinal severe acute respiratory syndrome coronavirus 2, revealing shared patterns of regulatory influence. An important role for the gut microbiota, including the virome, in regulating homeostasis and priming of intestinal IFN responses has also recently emerged.


Assuntos
Trato Gastrointestinal , Interações Hospedeiro-Patógeno , Interferon lambda , Interferon Tipo I , Interferons , Humanos , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/metabolismo , Interferons/imunologia , Animais , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/virologia , Trato Gastrointestinal/microbiologia , Imunidade Inata , Microbioma Gastrointestinal/imunologia , Viroses/imunologia
14.
Curr Opin Immunol ; 87: 102427, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38781720

RESUMO

The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.


Assuntos
Interferon lambda , Interferons , Viroses , Humanos , Interferons/metabolismo , Interferons/imunologia , Viroses/imunologia , Animais , Transdução de Sinais/imunologia , Fator de Transcrição STAT2/metabolismo , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/imunologia , Subunidade beta de Receptor de Interleucina-10/metabolismo
15.
Mol Immunol ; 170: 156-169, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38692097

RESUMO

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ligação a DNA , Fatores de Transcrição , Humanos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Feminino , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Recidiva Local de Neoplasia/imunologia , Interferons/metabolismo , Interferons/imunologia , Interferons/genética , Linhagem Celular Tumoral , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Animais , RNA de Cadeia Dupla/imunologia , Fator de Transcrição RelA/metabolismo , Camundongos , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/imunologia , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/imunologia
16.
J Virol ; 98(6): e0160423, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38780249

RESUMO

The global burden of disease caused by influenza B virus (IBV) is substantial; however, IBVs remain overlooked. Understanding host-pathogen interactions and establishing physiologically relevant models of infection are important for the development and assessment of therapeutics and vaccines against IBV. In this study, we assessed an upper respiratory tract (URT)-restricted model of mouse IBV infection, comparing it to the conventional administration of the virus to the total respiratory tract (TRT). We found that URT infections caused by different strains of IBV disseminate to the trachea but resulted in limited dissemination of IBV to the lungs. Infection of the URT did not result in weight loss or systemic inflammation even at high inoculum doses and despite robust viral replication in the nose. Dissemination of IBV to the lungs was enhanced in mice lacking functional type I IFN receptor (IFNAR2), but not IFNγ. Conversely, in mice expressing the IFN-inducible gene Mx1, we found reduced IBV replication in the lungs and reduced dissemination of IBV from the URT to the lungs. Inoculation of IBV in both the URT and TRT resulted in seroconversion against IBV. However, priming at the TRT conferred superior protection from a heterologous lethal IBV challenge compared to URT priming, as determined by improved survival rates and reduced viral replication throughout the respiratory tract. Overall, our study establishes a URT-restricted IBV infection model, highlights the critical role of IFNs in limiting dissemination of IBV to the lungs, and also demonstrates that the lack of viral replication in the lungs may impact protection from subsequent infections. IMPORTANCE: Our study investigated how influenza B virus (IBV) spreads from the nose to the lungs of mice and the impact this has on disease and protection from re-infection. We found that when applied to the nose only, IBV does not spread very efficiently to the lungs in a process controlled by the interferon response. Priming immunity at the nose only resulted in less protection from re-infection than priming immunity at both the nose and lungs. These insights can guide the development of potential therapies targeting the interferon response as well as of intranasal vaccines against IBV.


Assuntos
Vírus da Influenza B , Pulmão , Infecções por Orthomyxoviridae , Replicação Viral , Animais , Camundongos , Vírus da Influenza B/fisiologia , Vírus da Influenza B/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Pulmão/virologia , Pulmão/imunologia , Modelos Animais de Doenças , Interferons/metabolismo , Interferons/imunologia , Proteínas de Resistência a Myxovirus/metabolismo , Proteínas de Resistência a Myxovirus/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/deficiência , Camundongos Endogâmicos C57BL , Interações Hospedeiro-Patógeno/imunologia , Infecções Respiratórias/virologia , Infecções Respiratórias/imunologia , Feminino , Interferon gama/metabolismo , Traqueia/virologia
17.
Curr Opin Immunol ; 87: 102423, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38776716

RESUMO

The host immune response against severe acute respiratory syndrome coronavirus 2 includes the induction of a group of natural antiviral cytokines called interferons (IFNs). Although originally recognized for their ability to potently counteract infections, the mechanistic functions of IFNs in patients with varying severities of coronavirus disease 2019 (COVID-19) have highlighted a more complex scenario. Cellular and molecular analyses have revealed that timing, location, and subtypes of IFNs produced during severe acute respiratory syndrome coronavirus 2 infection play a major role in determining disease progression and severity. In this review, we summarize what the COVID-19 pandemic has taught us about the protective and detrimental roles of IFNs during the inflammatory response elicited against a new respiratory virus across different ages and its longitudinal consequences in driving the development of long COVID-19.


Assuntos
COVID-19 , Interferons , SARS-CoV-2 , Humanos , COVID-19/imunologia , Interferons/imunologia , Interferons/metabolismo , SARS-CoV-2/imunologia , Pandemias , Animais , Yin-Yang
18.
Curr Opin Immunol ; 87: 102426, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38795501

RESUMO

In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferon-stimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, including BST2, CD74, CH25H, DAXX, IFI6, IFITM1-3, LY6E, NCOA7, PLSCR1, OAS1, RTP4, and ZC3HAV1/ZAP, in restricting SARS-CoV-2 infection and discuss the virus's countermeasures. By synthesizing the latest research on SARS-CoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , COVID-19/imunologia , COVID-19/virologia , Internalização do Vírus , Interações Hospedeiro-Patógeno/imunologia , Replicação Viral , Animais , Antivirais/uso terapêutico , Interferons/metabolismo , Interferons/imunologia
19.
Mol Cell ; 84(11): 2087-2103.e8, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38815579

RESUMO

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo M , Íntrons , Elementos Nucleotídeos Longos e Dispersos , Splicing de RNA , RNA de Cadeia Dupla , Humanos , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , Elementos Nucleotídeos Longos e Dispersos/genética , Interferons/metabolismo , Interferons/genética , Animais , Células HEK293 , Camundongos , Transcriptoma , Éxons , Sítios de Splice de RNA , Elementos Alu/genética
20.
Microbiol Spectr ; 12(6): e0379623, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38712963

RESUMO

Cyclic GMP-AMP synthase (cGAS) is an important DNA pattern recognition receptor that senses double-stranded DNA derived from invading pathogens or self DNA in cytoplasm, leading to an antiviral interferon response. A tick-borne Bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), is an RNA virus that causes a severe emerging viral hemorrhagic fever in Asia with a high case fatality rate of up to 30%. However, it is unclear whether cGAS interacts with SFTSV infection. In this study, we found that SFTSV infection upregulated cGAS RNA transcription and protein expression, indicating that cGAS is an important innate immune response against SFTSV infection. The mechanism of cGAS recognizing SFTSV is by cGAS interacting with misplaced mitochondrial DNA in the cytoplasm. Depletion of mitochondrial DNA significantly inhibited cGAS activation under SFTSV infection. Strikingly, we found that SFTSV nucleoprotein (N) induced cGAS degradation in a dose-dependent manner. Mechanically, N interacted with the 161-382 domain of cGAS and linked the cGAS to LC3. The cGAS-N-LC3 trimer was targeted to N-induced autophagy, and the cGAS was degraded in autolysosome. Taken together, our study discovered a novel antagonistic mechanism of RNA viruses, SFTSV is able to suppress the cGAS-dependent antiviral innate immune responses through N-hijacking cGAS into N-induced autophagy. Our results indicated that SFTSV N is an important virulence factor of SFTSV in mediating host antiviral immune responses. IMPORTANCE: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne RNA virus that is widespread in East and Southeast Asian countries with a high fatality rate of up to 30%. Up to now, many cytoplasmic pattern recognition receptors, such as RIG-I, MDA5, and SAFA, have been reported to recognize SFTSV genomic RNA and trigger interferon-dependent antiviral responses. However, current knowledge is not clear whether SFTSV can be recognized by DNA sensor cyclic GMP-AMP synthase (cGAS). Our study demonstrated that cGAS could recognize SFTSV infection via ectopic mitochondrial DNA, and the activated cGAS-stimulator of interferon genes signaling pathway could significantly inhibit SFTSV replication. Importantly, we further uncovered a novel mechanism of SFTSV to inhibit innate immune responses by the degradation of cGAS. cGAS was degraded in N-induced autophagy. Collectively, this study illustrated a novel virulence factor of SFTSV to suppress innate immune responses through autophagy-dependent cGAS degradation.


Assuntos
Imunidade Inata , Nucleoproteínas , Nucleotidiltransferases , Phlebovirus , Phlebovirus/genética , Phlebovirus/imunologia , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Humanos , Nucleoproteínas/metabolismo , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Células HEK293 , Febre Grave com Síndrome de Trombocitopenia/virologia , Febre Grave com Síndrome de Trombocitopenia/imunologia , Febre Grave com Síndrome de Trombocitopenia/metabolismo , Autofagia , Animais , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Interferons/metabolismo , Interferons/imunologia , Interferons/genética , Proteínas Virais/metabolismo , Proteínas Virais/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...