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1.
Cell Host Microbe ; 27(3): 317-319, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32164842

RESUMO

Pathogens rely on nutrient assimilation, particularly essential metal incorporation, to successfully survive in the host. In this issue of Cell Host & Microbe, Riedelberger et al. (2020) convincingly demonstrate that type I interferons (IFNs-I) promote dysregulation of iron homeostasis in macrophages upon infection with Candida glabrata and exacerbate infection.


Assuntos
Candidíase , Interferon Tipo I , Candida glabrata , Homeostase , Humanos , Ferro
2.
Cell Host Microbe ; 27(3): 454-466.e8, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32075740

RESUMO

Type I interferons (IFNs-I) fulfil multiple protective functions during pathogenic infections, but they can also cause detrimental effects and enhance immunopathology. Here, we report that IFNs-I promote the dysregulation of iron homeostasis in macrophages during systemic infections with the intracellular pathogen Candida glabrata, leading to fungal survival and persistence. By engaging JAK1, IFNs-I disturb the balance of the transcriptional activator NRF2 and repressor BACH1 to induce downregulation of the key iron exporter Fpn1 in macrophages. This leads to enhanced iron accumulation in the phagolysosome and failure to restrict fungal access to iron pools. As a result, C. glabrata acquires iron via the Sit1/Ftr1 iron transporter system, facilitating fungal intracellular replication and immune evasion. Thus, IFNs-I are central regulators of iron homeostasis, which can impact infection, and restricting iron bioavailability may offer therapeutic strategies to combat invasive fungal infections.


Assuntos
Candida glabrata/patogenicidade , Homeostase , Interferon Tipo I/imunologia , Ferro/fisiologia , Macrófagos/microbiologia , Adulto , Animais , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Candidíase/imunologia , Proteínas de Transporte de Cátions/imunologia , Células Cultivadas , Feminino , Humanos , Evasão da Resposta Imune , Janus Quinase 1/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/imunologia , Fagossomos/microbiologia , Baço/imunologia
3.
PLoS One ; 15(1): e0218905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935222

RESUMO

The innate immune response induced by type I interferons (IFNs) plays a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNα/ß receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+ CXCR4+ T cells of HIV+ patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIV in vivo reside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNα subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV- individuals and in plasma samples of HIV+ patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+ patients compared to healthy donors, nor in LPMCs after HIV-1 infection ex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection are unlikely dictated by changes in IFNAR2 expression.


Assuntos
Infecções por HIV/genética , Imunidade Inata/genética , Receptor de Interferon alfa e beta/genética , Antivirais/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunidade nas Mucosas/imunologia , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Transdução de Sinais/efeitos dos fármacos
4.
Nat Commun ; 11(1): 524, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988324

RESUMO

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Células Dendríticas/imunologia , Poliovirus/imunologia , Animais , Vacinas Anticâncer , Vetores Genéticos/imunologia , Glioma/imunologia , Células HEK293 , Células HeLa , Humanos , Imunidade Inata , Imunoterapia/métodos , Interferon Tipo I/imunologia , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Poliovirus/genética
5.
Immunity ; 52(1): 109-122.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882361

RESUMO

Recent work suggests that cholesterol metabolism impacts innate immune responses against infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we have shown that upon DNA and RNA viral infection, macrophages reduced 7-dehydrocholesterol reductase (DHCR7) expression. DHCR7 deficiency or treatment with the natural product 7-dehydrocholesterol (7-DHC) could specifically promote phosphorylation of IRF3 (not TBK1) and enhance type I interferon (IFN-I) production in macrophages. We further elucidated that viral infection or 7-DHC treatment enhanced AKT3 expression and activation. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization. Deletion of DHCR7 and the DHCR7 inhibitors including AY9944 and the chemotherapy drug tamoxifen promoted clearance of Zika virus and multiple viruses in vitro or in vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeutics against emerging or highly pathogenic viruses.


Assuntos
Desidrocolesteróis/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/biossíntese , Macrófagos/imunologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Estomatite Vesicular/imunologia , Células A549 , Animais , Linhagem Celular , Colesterol/metabolismo , Ativação Enzimática/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/genética , Vírus da Estomatite Vesicular Indiana/imunologia
6.
Int J Cancer ; 146(2): 531-541, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31584185

RESUMO

We have developed an oncolytic Newcastle disease virus (NDV) that has potent in vitro and in vivo anti-tumor activities and attenuated pathogenicity in chickens. In this ex vivo study using the same recombinant NDV backbone with GFP transgene (NDV-GFP, designated as rNDV), we found that rNDV induces maturation of monocyte-derived immature dendritic cells (iDCs) by both direct and indirect mechanisms, which promote development of antigen-specific T cell responses. Addition of rNDV directly to iDCs culture induced DC maturation, as demonstrated by the increased expression of costimulatory and antigen-presenting molecules as well as the production of type I interferons (IFNs). rNDV infection of the HER-2 positive human breast cancer cell line (SKBR3) resulted in apoptotic cell death, release of proinflammatory cytokines, and danger-associated molecular pattern molecules (DAMPs) including high-mobility group protein B1 (HMGB1) and heat shock protein 70 (HSP70). Addition of rNDV-infected SKBR3 cells to iDC culture resulted in greatly enhanced upregulation of the maturation markers and release of type I IFNs by DCs than rNDV-infected DCs only. When co-cultured with autologous T cells, DCs pre-treated with rNDV-infected SKBR3 cells cross-primed T cells in an antigen-specific manner. Altogether, our data strongly support the potential of oncolytic NDV as efficient therapeutic agent for cancer treatment.


Assuntos
Apresentação Cruzada , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Animais , Técnicas de Cocultura , Células Dendríticas/metabolismo , Feminino , Células HeLa , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Neoplasias/imunologia , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , RNA/administração & dosagem , RNA/genética , RNA Viral/administração & dosagem , RNA Viral/genética , Linfócitos T/imunologia , Células Vero
7.
BMC Infect Dis ; 19(1): 1031, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801478

RESUMO

BACKGROUND: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. METHODS: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. RESULTS: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. CONCLUSIONS: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.


Assuntos
Interferon Tipo I/metabolismo , Mycobacterium bovis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Animais , Anticorpos/farmacologia , Citocinas/metabolismo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/efeitos dos fármacos
8.
Nat Cell Biol ; 21(12): 1604-1614, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792381

RESUMO

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor-TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1-TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1-TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Tolerância Imunológica/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Células A549 , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Células Cultivadas , Células Epiteliais/patologia , Células HEK293 , Humanos , Imunidade Inata/genética , Interferon Tipo I/genética , Pulmão/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL
9.
Immunity ; 51(6): 1074-1087.e9, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31784108

RESUMO

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon Tipo I/imunologia , Fígado/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Receptor de Interferon alfa e beta/metabolismo , Animais , Arginina/sangue , Linhagem Celular , Cricetinae , Feminino , Hepatócitos/metabolismo , Fígado/imunologia , Fígado/virologia , Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ornitina/sangue , Ornitina Carbamoiltransferase/genética , Transdução de Sinais/imunologia , Ureia/metabolismo , Células Vero
10.
PLoS Pathog ; 15(12): e1008239, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31877196

RESUMO

Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.


Assuntos
Medula Óssea/virologia , Vírus da Ectromelia/patogenicidade , Ectromelia Infecciosa/virologia , Nucleotídeos Cíclicos/metabolismo , Animais , Medula Óssea/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Interferon Tipo I/metabolismo , Camundongos Transgênicos , Nucleotidiltransferases/genética , Proteínas Serina-Treonina Quinases/metabolismo
11.
Vet Microbiol ; 239: 108460, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31767079

RESUMO

Newcastle disease (ND) is an acute and contagious avian disease caused by Newcastle disease virus (NDV). MicroRNAs (miRNAs) play a significant role in host-pathogen interactions and the innate immune response. However, the role of miRNAs in the host response to NDV infection is not clearly understood. In this study, we showed that expression of the cellular miRNA gga-miR-455-5p was downregulated in vivo and in vitro in response to NDV infection. Next, we found that the transfection of chicken embryonic fibroblasts (CEFs) with gga-miR-455-5p suppressed NDV replication, while the blockade of endogenous gga-miR-455-5p expression with inhibitors enhanced NDV replication. In addition, gga-miR-455-5p enhanced the expression of type I interferon and the interferon-inducible genes (ISGs) OASL and Mx1 by targeting SOCS3, a negative regulator of type I IFN signaling. Altogether, these findings highlight the crucial role of gga-miR-455-5p in host defense against NDV by targeting the SOCS3 gene to inhibit NDV replication.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Vírus da Doença de Newcastle/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Replicação Viral/genética , Animais , Células Cultivadas , Regulação para Baixo , Fibroblastos/virologia , Interações entre Hospedeiro e Microrganismos/genética , Interferon Tipo I/genética , Doença de Newcastle/fisiopatologia , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/genética , Transdução de Sinais/genética
13.
Adv Exp Med Biol ; 1209: 125-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728868

RESUMO

The production of type I interferons (IFNs) is one of the hallmarks of intracellular antimicrobial program. Typical type I IFN response activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which results in the transcription of plentiful IFN-stimulated genes (ISGs) to establish the comprehensive antiviral states. Type I IFN signaling should initiate timely to provoke innate and adaptive immune responses for effective elimination of the invading pathogens. Meanwhile, a precise control must come on the stage to restrain the persistent activation of type I IFN responses to avoid attendant toxicity. Autophagy, a conserved eukaryotic degradation system, mediated by a number of autophagy-related (ATG) proteins, plays an essential role in the clearance of invading microorganism and manipulation of type I responses. Autophagy modulates type I IFN responses through regulatory integration with innate immune signaling pathways, and by removing endogenous ligands of innate immune sensors. Moreover, selective autophagy governs the choice of innate immune factors as specific cargoes for degradation, thus tightly monitoring the type I IFN responses. This review will focus on the cross-regulation between autophagy and type I IFN signaling in host defense.


Assuntos
Autofagia , Interações Hospedeiro-Patógeno , Interferon Tipo I , Transdução de Sinais , Animais , Autofagia/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/imunologia
14.
Nat Immunol ; 20(12): 1574-1583, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31745335

RESUMO

Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak-STAT signaling pathway and induce overlapping patterns of expression, called 'interferon signatures', of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an 'interferon epigenomic signature' by activating latent enhancers and 'bookmarking' chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.


Assuntos
Doenças Autoimunes/imunologia , Epigênese Genética/imunologia , Inflamação/imunologia , Interferon Tipo I/metabolismo , Animais , Autoimunidade , Homeostase , Humanos , Tolerância Imunológica , Interferon Tipo I/genética , Janus Quinases/metabolismo , Ativação Linfocitária , NF-kappa B/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Transcriptoma
15.
Nat Cell Biol ; 21(11): 1346-1356, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31685995

RESUMO

In the past two decades, emerging studies have suggested that DExD/H box helicases belonging to helicase superfamily 2 (SF2) play essential roles in antiviral innate immunity. However, the antiviral functions of helicase SF1, which shares a conserved helicase core with SF2, are little understood. Here we demonstrate that zinc finger NFX1-type containing 1 (ZNFX1), a helicase SF1, is an interferon (IFN)-stimulated, mitochondrial-localised dsRNA sensor that specifically restricts the replication of RNA viruses. Upon virus infection, ZNFX1 immediately recognizes viral RNA through its Armadillo-type fold and P-loop domain and then interacts with mitochondrial antiviral signalling protein to initiate the type I IFN response without depending on retinoic acid-inducible gene I-like receptors (RLRs). In short, as is the case with interferon-stimulated genes (ISGs) alone, ZNFX1 can induce IFN and ISG expression at an early stage of RNA virus infection to form a positively regulated loop of the well-known RLR signalling. This provides another layer of understanding of the complexity of antiviral immunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Mitocôndrias/imunologia , Fatores de Processamento de RNA/genética , RNA de Cadeia Dupla/genética , RNA Viral/genética , Vesiculovirus/genética , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/imunologia , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/virologia , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/virologia , Conformação de Ácido Nucleico , Poli I-C/farmacologia , Cultura Primária de Células , Ligação Proteica , Fatores de Processamento de RNA/imunologia , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/imunologia , RNA Viral/química , RNA Viral/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Vesiculovirus/crescimento & desenvolvimento , Vesiculovirus/imunologia
16.
PLoS Pathog ; 15(10): e1008060, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658294

RESUMO

The loss of Memory CD4 T-cells (Mem) is a major hallmark of HIV-1 immuno-pathogenesis and occurs early during the first months of primary infection. A lot of effort has been put into understanding the molecular mechanisms behind this loss, yet they still have not been fully identified. In this study, we unveil the unreported role of USP18 in the deleterious effects of sustained type I IFN signaling on Mem, including HIV-1-specific CD4 T-cells. We find that interfering with IFN-I signaling pathway in infected patients, notably by targeting the interferon-stimulated gene USP18, resulted in reduced PTEN expression similar to those observed in uninfected control donors. We show that AKT activation in response to cytokine treatment, T-cell receptor (TcR) triggering, as well as HIV-1 Gag stimulation was significantly improved in infected patients when PTEN or USP18 were inhibited. Finally, our data demonstrate that higher USP18 in Mem from infected patients prevent proper cell survival and long-lasting maintenance in an AKT-dependent manner. Altogether, we establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Mem and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , HIV-1/imunologia , Memória Imunológica/imunologia , Interferon Tipo I/imunologia , PTEN Fosfo-Hidrolase/biossíntese , Ubiquitina Tiolesterase/metabolismo , Apoptose/imunologia , Sobrevivência Celular , Infecções por HIV/imunologia , Infecções por HIV/patologia , HIV-1/patogenicidade , Humanos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Ubiquitina Tiolesterase/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
17.
J Immunol Res ; 2019: 5370706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583257

RESUMO

MHC class I molecules are key in the presentation of antigen and initiation of adaptive CD8+ T cell responses. In addition to its classical activity, MHC I may possess nonclassical functions. We have previously identified a regulatory role of MHC I in TLR signaling and antibacterial immunity. However, its role in innate antiviral immunity remains unknown. In this study, we found a reduced viral load in MHC I-deficient macrophages that was independent of type I IFN production. Mechanically, MHC I mediated viral suppression by inhibiting the type I IFN signaling pathway, which depends on SHP2. Cross-linking MHC I at the membrane increased SHP2 activation and further suppressed STAT1 phosphorylation. Therefore, our data revealed an inhibitory role of MHC I in type I IFN response to viral infection and expanded our understanding of MHC I and antigen presentation.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Transdução de Sinais , Viroses/metabolismo , Viroses/virologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Interferon Tipo I/metabolismo , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Viroses/imunologia , Replicação Viral
18.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575039

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates inflammation and immunity. Knowledge of its regulatory mechanisms is very limited. Here, we showed that enterovirus 71 (EV71) infection induced the phosphorylation of STAT3 and the expression of its downstream inflammatory regulators. Knockdown of STAT3 with siRNAs significantly restricted viral RNA and protein levels, and also reduced viral titers. With further investigation, we found that importin α family member Karyopherin-α1 (KPNA1) was employed by both STAT1 and STAT3 for their nuclear import. The phosphorylated and un-phosphorylated STAT3 competed with STAT1 for binding to the decreased KPNA1 post infection and repressed downstream ISG expression. STAT3 knockdown alleviated the repressed type I IFN-mediated antiviral response upon infection and led to decreased viral replication. Taken together, our data suggested the role of STAT3 in maintaining the balance of inflammation and antiviral responses in the central nervous system (CNS) upon infection.


Assuntos
Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Viroses/metabolismo , Transporte Ativo do Núcleo Celular , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Viroses/virologia
19.
Nat Commun ; 10(1): 4700, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619669

RESUMO

The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36ß deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.


Assuntos
Herpes Simples/imunologia , Interferon Tipo I/imunologia , Interleucina-1/imunologia , Receptor de Interferon alfa e beta/genética , Animais , Modelos Animais de Doenças , Herpesvirus Humano 1 , Humanos , Evasão da Resposta Imune , Fator Regulador 1 de Interferon/imunologia , Interleucina-1/genética , Queratinócitos , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Regulação para Cima
20.
PLoS Pathog ; 15(10): e1008062, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31585000

RESUMO

Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.


Assuntos
Antivirais/farmacologia , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Interferon Tipo I/metabolismo , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Progranulinas/fisiologia , Animais , Células Cultivadas , Regulação para Baixo , Interações Hospedeiro-Patógeno , Masculino , Camundongos , Camundongos Knockout , NF-kappa B , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Transdução de Sinais
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