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1.
Vet Immunol Immunopathol ; 212: 15-22, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213247

RESUMO

Marek's disease virus (MDV), an α-herpesvirus targeting avian species, causes fatal Marek's disease (MD) in chickens. The host interferon (IFN) responses play a key role in resisting viral infection. However, host IFN responses following MDV infection in the chicken central immune organs (thymus and bursa of Fabricius), which contain numerous MDV target cells, is poorly understood. In this study, we performed animal experiments in specific pathogen-free chickens infected with two virulent MDV strains (BS/15 and Md5) or without infection as negative controls. Specifically, the type I IFN (IFN-α and IFN-ß) transcriptional and proteomic expression levels at 7, 10, 14, 17, and 21 days post infection (dpi) were detected and analyzed. Our results indicated that the mRNA and protein expression levels of IFN-α and IFN-ß in the thymus and bursa of Fabricius were mainly downregulated in cytolytic infection (such as 10 dpi) and reactivation (such as 17 dpi) stages, but not the latent (such as 14 dpi) stage of MDV infection, which was determined by comprehensively analyzing the MDV viral load and immune organ damage caused by MDV infection. These data suggest that MDV could inhibit the expression of host type I IFNs, which may be involved in the MDV-induced host immunosuppression and contribute to the immune escape of MDV from host immunity. Furthermore, we found that the downregulated expression of the host type I IFNs induced by BS/15 and Md5 infection was significantly different, which we speculated may be related to the diverse virulence and pathogenicity of MDV strains. In conclusion, our study demonstrated that MDV mostly inhibited the expression of type I IFNs in infected hosts, which may be associated to its pathogenesis.


Assuntos
Interferon Tipo I/imunologia , Doença de Marek/imunologia , Doenças das Aves Domésticas/imunologia , Animais , Bolsa de Fabricius/imunologia , Galinhas , Expressão Gênica , Herpesvirus Galináceo 2 , Interferon Tipo I/genética , Interferon-alfa/genética , Interferon-alfa/imunologia , Interferon beta/genética , Interferon beta/imunologia , Doenças das Aves Domésticas/virologia , Proteômica , RNA Mensageiro/genética , Organismos Livres de Patógenos Específicos , Timo/imunologia , Carga Viral , Virulência
2.
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
3.
J Immunol Res ; 2019: 7596786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049360

RESUMO

Type I interferon (IFN-I) plays a critical role in the antitumor immune response. In our previous study, we showed that IFN-I-inducible 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulated IFN-I production upon tumor challenge similar to that of viral infection. Thus, OASL1-deficient (Oasl1 -/-) mice were more resistant to implanted tumor growth than wild-type (WT) mice. In this study, we investigated whether targeting or suppressing OASL1 could show synergistic effects on tumor clearance with conventional cancer therapies (such as chemotherapy and radiotherapy) using Oasl1 -/- mice and a transplantable lung metastatic tumor cell model. Upon treatment with the anticancer drug cisplatin, we found that Oasl1 -/- mice showed enhanced resistance to injected tumors compared to untreated Oasl1 -/- mice. Similarly, irradiated Oasl1 -/- mice showed better resistance to tumor challenge than untreated Oasl1 -/- mice. Additionally, we found that Oasl1 -/- mice applied with both types of the cancer therapies contained more cytotoxic effector cells, such as CD8+ T cells and NK cells, and produced more cytotoxic effector cytokine IFN-γ as well as IFN-I in their tumor-containing lungs compared to untreated Oasl1 -/- mice. Collectively, these results show that targeting OASL1 together with conventional cancer therapies could be an effective strategy to enhance treatment efficacy.


Assuntos
2',5'-Oligoadenilato Sintetase/antagonistas & inibidores , Cisplatino/uso terapêutico , Interferon Tipo I/imunologia , Neoplasias Pulmonares/imunologia , 2',5'-Oligoadenilato Sintetase/genética , Animais , Antineoplásicos , Interferon gama/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Metástase Neoplásica
4.
J Immunol Res ; 2019: 8685312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089479

RESUMO

Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Infecções por HIV/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interferon Tipo I/imunologia , Transdução de Sinais , Síndrome de Imunodeficiência Adquirida/virologia , Animais , Ensaios Clínicos como Assunto , HIV/imunologia , Humanos , Imunidade Inata , Camundongos
5.
J Immunol Res ; 2019: 1749803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093508

RESUMO

Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Imiquimode/farmacologia , Glicoproteínas de Membrana/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Animais , Feminino , Imidazóis/farmacologia , Indutores de Interferon/farmacologia , Interferon Tipo I/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/farmacologia , Tiazóis/farmacologia
6.
Fish Shellfish Immunol ; 91: 78-86, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31039439

RESUMO

Type I interferons, as a class of multipotent cytokines, play a key role in host antiviral immune responses. In this study, a type I IFN coding gene of gibel carp, Carassius auratus gibelio, CagIFNa was cloned and sequenced. The full-length cDNA sequence of CagIFNa consists of 724 nucleotides that encode a predicted protein of 183 amino acids. CagIFNa has two highly conserved cysteine residues in the deduced protein, which is mostly conserved in the fish group I type I IFNs. CagIFNa was identified as a member of the IFNa subgroup of group I type I IFNs by phylogenetic analysis. CagIFNa transcripts were detected in all investigated tissues with higher levels in the liver, intestine, spleen and head kidney of gibel carp. Following injection with Cyprinid herpesvirus 2 (CyHV-2), CagIFNa gene expression was significantly inhibited in the spleen but delayed and then increased in head kidneys. Similarly, while CagIFNa expression was rapidly induced in gibel carp brain (GiCB) cells by poly I:C stimulation and its high induction level was delayed following CyHV-2 infection. CagIFNa overexpression in GiCB cells drastically reduced virus CPE and titer. Furthermore, several genes associated with type I IFN signaling pathway including IRF3, IRF7, IRF9, STAT1, Mx1 and PKR were induced in GiCB cells overexpressing CagIFNa upon CyHV-2 infection. These results show that CagIFNa plays a role in antiviral immune system in gibel carp.


Assuntos
Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Carpa Dourada/genética , Carpa Dourada/imunologia , Imunidade Inata/genética , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Herpesviridae , Infecções por Herpesviridae/imunologia , Interferon Tipo I/química , Filogenia , Poli I-C/farmacologia , Distribuição Aleatória , Alinhamento de Sequência/veterinária
7.
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
8.
Immunity ; 50(4): 907-923, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995506

RESUMO

Type I interferons (IFNs) (IFN-α, IFN-ß) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.


Assuntos
Interferon Tipo I/imunologia , Interferons/imunologia , Imunidade Adaptativa , Animais , Antivirais/uso terapêutico , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Células Epiteliais/imunologia , Feminino , Humanos , Interferon Tipo I/efeitos adversos , Interferon Tipo I/uso terapêutico , Interferons/efeitos adversos , Interferons/uso terapêutico , Masculino , Troca Materno-Fetal/imunologia , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Especificidade de Órgãos , Gravidez , Transdução de Sinais/imunologia , Transcrição Genética , Transcriptoma , Viroses/tratamento farmacológico , Viroses/imunologia
9.
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
10.
Nat Microbiol ; 4(6): 914-924, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936491

RESUMO

Interferon (IFN)-mediated antiviral responses are central to host defence against viral infection. Despite the existence of at least 20 IFNs, there are only three known cell surface receptors. IFN signalling and viral evasion mechanisms form an immensely complex network that differs across species. In this Review, we begin by highlighting some of the advances that have been made towards understanding the complexity of differential IFN signalling inputs and outputs that contribute to antiviral defences. Next, we explore some of the ways viruses can interfere with, or circumvent, these defences. Lastly, we address the largely under-reviewed impact of IFN signalling on host tropism, and we offer perspectives on the future of research into IFN signalling complexity and viral evasion across species.


Assuntos
Evasão da Resposta Imune/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Transdução de Sinais/imunologia , Viroses/imunologia , Animais , Antivirais , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Evasão da Resposta Imune/fisiologia , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Interferon Tipo I/genética , Interferon Tipo I/fisiologia , Interferons/genética , Interferons/fisiologia , Transdução de Sinais/fisiologia , Tropismo , Vírus/imunologia
11.
Viral Immunol ; 32(3): 131-143, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30822217

RESUMO

Influenza A viruses (IAVs) have multiple mechanisms for altering the host immune response to aid in virus survival and propagation. While both type I and II interferons (IFNs) have been associated with increased bacterial superinfection (BSI) susceptibility, we found that in some cases type I IFNs can be beneficial for BSI outcome. Specifically, we have shown that antagonism of the type I IFN response during infection by some IAVs can lead to the development of deadly BSI. The nonstructural protein 1 (NS1) from IAV is well known for manipulating host type I IFN responses, but the viral proteins mediating BSI severity remain unknown. In this study, we demonstrate that the PDZ-binding motif (PDZ-bm) of the NS1 C-terminal region from mouse-adapted A/Puerto Rico/8/34-H1N1 (PR8) IAV dictates BSI susceptibility through regulation of IFN-α/ß production. Deletion of the NS1 PDZ-bm from PR8 IAV (PR8-TRUNC) resulted in 100% survival and decreased bacterial burden in superinfected mice compared with 0% survival in mice superinfected after PR8 infection. This reduction in BSI susceptibility after infection with PR8-TRUNC was due to the presence of IFN-ß, as protection from BSI was lost in Ifn-ß-/- mice, resembling BSI during PR8 infection. PDZ-bm in PR8-infected mice inhibited the production of IFN-ß posttranscriptionally, and both delayed and reduced expression of the tunable interferon-stimulated genes. Finally, a similar lack of BSI susceptibility, due to the presence of IFN-ß on day 7 post-IAV infection, was also observed after infection of mice with A/TX98-H3N2 virus that naturally lacks a PDZ-bm in NS1, indicating that this mechanism of BSI regulation by NS1 PDZ-bm may not be restricted to PR8 IAV. These results demonstrate that the NS1 C-terminal PDZ-bm, like the one present in PR8 IAV, is involved in controlling susceptibility to BSI through the regulation of IFN-ß, providing new mechanisms for NS1-mediated manipulation of host immunity and BSI severity.


Assuntos
Infecções por Orthomyxoviridae/veterinária , Domínios PDZ/genética , Superinfecção/microbiologia , Proteínas não Estruturais Virais/genética , Animais , Cães , Regulação da Expressão Gênica , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon beta/genética , Interferon beta/imunologia , Células Madin Darby de Rim Canino , Infecções por Orthomyxoviridae/virologia , Replicação Viral
12.
PLoS Pathog ; 15(2): e1007589, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30818370

RESUMO

Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon production. Here, we demonstrated that pDCs produce type I interferons upon physical cell contact with HTLV-infected cells, yet pDC activation inversely correlates with the ability of the HTLV-producing cells to transmit infection. We show that pDCs sense surface associated-HTLV present with glycan-rich structure referred to as biofilm-like structure, which thus represents a newly described viral structure triggering the antiviral response by pDCs. Consistently, heparan sulfate proteoglycans and especially the cell surface pattern of terminal ß-galactoside glycosylation, modulate the transmission of the immunostimulatory RNA to pDCs. Altogether, our results uncover a function of virus-containing cell surface-associated glycosylated structures in the activation of innate immunity.


Assuntos
Células Dendríticas/fisiologia , Infecções por HTLV-I/metabolismo , Citocinas , Galactosídeos/metabolismo , Glicosilação , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Vírus Linfotrópico T Tipo 2 Humano/imunologia , Vírus Linfotrópico T Tipo 2 Humano/patogenicidade , Humanos , Imunidade Inata/fisiologia , Interferon Tipo I/imunologia , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Células Jurkat , Linfócitos T/imunologia , Linfócitos T/fisiologia
13.
Viruses ; 11(2)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791575

RESUMO

Over the past decades, infection of mice with lymphocytic choriomeningitis virus (LCMV) has provided an invaluable insight into our understanding of immune responses to viruses. In particular, this model has clarified the central roles that type I interferons play in initiating and regulating host responses. The use of different strains of LCMV and routes of infection has allowed us to understand how type I interferons are critical in controlling virus replication and fostering effective antiviral immunity, but also how they promote virus persistence and functional exhaustion of the immune response. Accordingly, these discoveries have formed the foundation for the development of novel treatments for acute and chronic viral infections and even extend into the management of malignant tumors. Here we review the fundamental insights into type I interferon biology gained using LCMV as a model and how the diversity of LCMV strains, dose, and route of administration have been used to dissect the molecular mechanisms underpinning acute versus persistent infection. We also identify gaps in the knowledge regarding LCMV regulation of antiviral immunity. Due to its unique properties, LCMV will continue to remain a vital part of the immunologists' toolbox.


Assuntos
Interferon Tipo I/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Doença Aguda , Imunidade Adaptativa , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Ensaios Clínicos como Assunto , Humanos , Imunidade Inata , Camundongos , Camundongos Knockout , Transdução de Sinais , Replicação Viral
14.
Nat Commun ; 10(1): 863, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787294

RESUMO

The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-level analysis of HIV-1 negative vaccinees reveals that type I interferons that activate the IRF7 antiviral program and type II interferon-stimulated genes implicated in antigen-presentation are both associated with a reduced risk of HIV-1 acquisition. In contrast, genes upstream and downstream of NF-κB, mTORC1 and host genes required for viral infection are associated with an increased risk of HIV-1 acquisition among vaccinees and placebo recipients, defining a vaccine independent association with HIV-1 acquisition. Our transcriptomic analysis of RV144 trial samples identifies IRF7 as a mediator of protection and the activation of mTORC1 as a correlate of the risk of HIV-1 acquisition.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon gama/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Humanos , Imunização , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , NF-kappa B/metabolismo , Placebos/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
15.
Viruses ; 11(2)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769920

RESUMO

RNA virus invasion induces a cytosolic RIG-I-like receptor (RLR) signaling pathway by promoting assembly of the Mitochondrial antiviral-signaling protein (MAVS) signalosome and triggers the rapid production of type I interferons (IFNs) and proinflammatory cytokines. During this process, the pivotal kinase TANK binding kinase 1 (TBK1) is recruited to the MAVS signalosome to transduce a robust innate antiviral immune response by phosphorylating transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB and promoting their nuclear translocation. However, the molecular mechanisms underlying the negative regulation of TBK1 are largely unknown. In the present study, we found that THO complex subunit 7 homolog (THOC7) negatively regulated the cellular antiviral response by promoting the proteasomal degradation of TBK1. THOC7 overexpression potently inhibited Sendai virus- or polyI:C-induced IRF3 dimerization and phosphorylation and IFN-ß production. In contrast, THOC7 knockdown had the opposite effects. Moreover, we simulated a node-activated pathway to show that THOC7 regulated the RIG-I-like receptors (RLR)-/MAVS-dependent signaling cascade at the TBK1 level. Furthermore, THOC7 was involved in the MAVS signalosome and promoted TBK1 degradation by increasing its K48 ubiquitin-associated polyubiquitination. Together, these findings suggest that THOC7 negatively regulates type I IFN production by promoting TBK1 proteasomal degradation, thus improving our understanding of innate antiviral immune responses.


Assuntos
Imunidade Celular , Imunidade Inata , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Vírus Sendai/imunologia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/imunologia , Células MCF-7 , Fosforilação , Complexo de Endopeptidases do Proteassoma/imunologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a RNA/genética , Vírus Sendai/genética , Transdução de Sinais , Ubiquitina/metabolismo , Ubiquitinação
16.
Fish Shellfish Immunol ; 87: 809-819, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776543

RESUMO

Carp from breeding strains with different genetic background present diverse levels of resistance to viral pathogens. Carp strains of Asian origin, currently being treated as Cyprinus rubrofuscus L., especially Amur wild carp (AS), were proven to be more resistant to koi herpesvirus disease (KHVD; caused by cyprinid herpesvirus 3, CyHV-3) than strains originating from Europe and belonging to Cyprinus carpio L., like the Prerov scale carp (PS) or koi carp from a breed in the Czech Republic. We hypothesised that it can be associated with a higher magnitude of type I interferon (IFN) response as a first line of innate defence mechanisms against viral infections. To evaluate this hypothesis, four strains of common carp (AS, Rop, PS and koi) were challenged using two viral infection models: Rhabdovirus SVCV (spring viremia of carp virus) and alloherpesvirus CyHV-3. The infection with SVCV induced a low mortality rates and the most resistant was the Rop strain (no mortalities), whereas the PS strain was the most susceptible (survival rate of 78%). During CyHV-3 infection, Rop and AS strains performed better (survival rates of 78% and 53%, respectively) than PS and koi strains (survival rates of 35% and 10%, respectively). The evaluation of virus loads and virus replication showed significant differences between the carp strains, which correlated with the mortality rate. The evaluation of type I IFN responses showed that there were fundamental differences between the virus infection models. While responses to the SVCV were high, the CyHV-3 generally induced low responses. Furthermore, the results demonstrated that the magnitude of type I IFN responses did not correlate with a higher resistance in infected carp. In the case of a CyHV-3 infection, reduced type I IFN responses could be related to the potential ability of the virus to interfere with cellular sensing of foreign nucleic acids. Taken together, the results broaden our understanding of how common carp from different genetic strains interact with various viral pathogens.


Assuntos
Carpas/genética , Carpas/imunologia , Resistência à Doença/genética , Doenças dos Peixes/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Herpesviridae/fisiologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária
17.
Viruses ; 11(2)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717138

RESUMO

Autophagy exhibits dual effects during viral infections, promoting the clearance of viral components and activating the immune system to produce antiviral cytokines. However, some viruses impair immune defenses by collaborating with autophagy. Mounting evidence suggests that the interaction between autophagy and innate immunity is critical to understanding the contradictory roles of autophagy. Type I interferon (IFN-I) is a crucial antiviral factor, and studies have indicated that autophagy affects IFN-I responses by regulating IFN-I and its receptors expression. Similarly, IFN-I and interferon-stimulated gene (ISG) products can harness autophagy to regulate antiviral immunity. Crosstalk between autophagy and IFN-I responses could be a vital aspect of the molecular mechanisms involving autophagy in innate antiviral immunity. This review briefly summarizes the approaches by which autophagy regulates antiviral IFN-I responses and highlights the recent advances on the mechanisms by which IFN-I and ISG products employ autophagy against viruses.


Assuntos
Autofagia/imunologia , Interações Hospedeiro-Patógeno , Imunidade Inata , Interferon Tipo I/imunologia , Viroses/imunologia , Regulação da Expressão Gênica , Humanos , Interferon-alfa/imunologia , Interferon beta/imunologia , Transdução de Sinais/imunologia
18.
Nat Immunol ; 20(2): 152-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643259

RESUMO

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.


Assuntos
Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Animais , Cercopithecus aethiops , Pré-Escolar , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Imunidade Inata , Células Jurkat , Macrófagos , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Células NIH 3T3 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Cultura Primária de Células , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Células Vero
19.
J Immunol ; 202(4): 1112-1123, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30635395

RESUMO

CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição Ikaros/imunologia , Inflamação/imunologia , Animais , Feminino , Fator de Transcrição Ikaros/deficiência , Fator de Transcrição Ikaros/genética , Inflamação/genética , Interferon Tipo I/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação
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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