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1.
Cell Rep ; 35(7): 109126, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33974846

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.


Assuntos
COVID-19/virologia , SARS-CoV-2/imunologia , Proteínas Virais/imunologia , Animais , Antivirais/farmacologia , Autofagossomos/imunologia , Autofagia/imunologia , COVID-19/imunologia , Linhagem Celular , Chlorocebus aethiops , Exorribonucleases/imunologia , Células HEK293 , Células HeLa , Humanos , Evasão da Resposta Imune , Imunidade Inata , Interferon Tipo I/metabolismo , Interferons/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , SARS-CoV-2/patogenicidade , Células Vero , Proteínas não Estruturais Virais/imunologia
2.
Elife ; 102021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34047696

RESUMO

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.


Assuntos
Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Imunidade nas Mucosas , Interferon Tipo I/metabolismo , Interleucina-18/metabolismo , Membrana Mucosa/virologia , Ativação de Neutrófilo , Neutrófilos/virologia , Vagina/virologia , Animais , Anticorpos/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Herpes Genital/metabolismo , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/imunologia , Interações Hospedeiro-Patógeno , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/inervação , Membrana Mucosa/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Células Vero
3.
Front Immunol ; 12: 652965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912177

RESUMO

Type I IFNs, such as interferon alpha and interferon beta, are key regulators of the adaptive immune response during infectious diseases. Type I IFNs are induced upon infection, bind interferon α/ß receptors on T-cells and activate intracellular pathways. The activating and inhibitory consequences of type I IFN-signaling are determined by cell type and cellular environment. The neonatal immune system is associated with increased vulnerability to infectious diseases which could partly be explained by an immature CD4+ T-cell compartment. Here, we show low IFN-ß-mediated inhibition of CD4+ T-cell proliferation, phosphorylation of retinoblastoma protein and cytokine production in human newborns compared to adults. In addition, both naïve and total newborn CD4+ T-cells are unable to induce the cell-cycle inhibitor p21 upon exposure to IFN-ß in contrast to adults. The distinct IFN-ß-signaling in newborns provides novel insights into T cell functionality and regulation of T cell-dependent inflammation during early life immune responses.


Assuntos
Imunidade Adaptativa/fisiologia , Linfócitos T CD4-Positivos/imunologia , Inibidor de Quinase Dependente de Ciclina p21/deficiência , Interferon beta/metabolismo , Transdução de Sinais/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Adulto , Fatores Etários , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sangue Fetal/citologia , Sangue Fetal/imunologia , Citometria de Fluxo , Humanos , Separação Imunomagnética , Recém-Nascido , Cultura Primária de Células , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Nature ; 591(7848): 124-130, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33494096

RESUMO

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/fisiopatologia , Interferons/antagonistas & inibidores , Interferons/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Anticorpos Antivirais/sangue , Formação de Anticorpos , Sequência de Bases , COVID-19/sangue , COVID-19/virologia , Feminino , Humanos , Imunoglobulina G/imunologia , Interferons/metabolismo , Masculino , Neutrófilos/imunologia , Neutrófilos/patologia , Domínios Proteicos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Receptores de IgG/imunologia , Análise de Célula Única , Carga Viral/imunologia
5.
Lupus ; 29(14): 1845-1853, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32960720

RESUMO

OBJECTIVE: The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. METHODS: A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. RESULTS: Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88-7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. CONCLUSION: This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos , Humanos , Interferon Tipo I/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor de Interferon alfa e beta/antagonistas & inibidores
6.
Virology ; 549: 25-31, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32818729

RESUMO

It has been reported worldwide that the Zika virus (ZIKV) could be transmitted through placentas and sexual contact. ZIKV can also cause Guillain-Barre syndrome, microcephaly and neurological abnormalities. However, there are no approved vaccines available. We constructed six DNA vaccine candidates and tested the immunogenicity. Tandem repeated envelope domain Ⅲ (ED Ⅲ × 3) induced highly total IgG and neutralization antibody, as well as CD8+ T cell responses. Also, stem region-removed envelope (E ΔSTEM) elicited a robust production of IFN-γ in mice. To examine in vivo protection, we used mice treated with an IFNAR1 blocking antibody before and after the challenge. Vaccination with the two candidates led to a decline in the level of viral RNAs in organs. Moreover, the sera from the vaccinated mice did not enhance the infection of Dengue virus in K562 cells. These findings suggest the potential for the development of a novel ZIKV DNA vaccine.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas de DNA/biossíntese , Proteínas do Envelope Viral/imunologia , Vacinas Virais/biossíntese , Infecção por Zika virus/prevenção & controle , Zika virus/efeitos dos fármacos , Animais , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Chlorocebus aethiops , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/crescimento & desenvolvimento , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Imunogenicidade da Vacina , Células K562 , Camundongos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Células Vero , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Zika virus/genética , Zika virus/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
7.
Immunohorizons ; 4(2): 93-107, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32086319

RESUMO

TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 are normally part of the antiviral defense response, but they have also been implicated as drivers of autoimmune diseases such as lupus. The receptors have slightly different ligand-binding specificities and cellular expression patterns that suggest they have nonredundant specialized roles. How the roles of TLR7 and TLR8 differ may be determined by which cell types express each TLR and how the cells respond to activation of each receptor. To provide a better understanding of the effects of TLR7/8 activation, we have characterized changes induced by TLR-specific agonists in different human immune cell types and defined which responses are a direct consequence of TLR7 or TLR8 activation and which are secondary responses driven by type I IFN or cytokines produced subsequent to the primary response. Using cell sorting, gene expression analysis, and intracellular cytokine staining, we have found that the IFN regulatory factor (IRF) and NF-κB pathways are differentially activated downstream of the TLRs in various cell types. Studies with an anti-IFNAR Ab in human cells and lupus mice showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-κB-regulated genes induced directly by TLR7/8 activation at earlier timepoints. In summary, these results elucidate the different roles TLR7 and TLR8 play in immunity and inform strategies for potential treatment of autoimmune diseases driven by TLR7/8 activation.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Animais , Autoanticorpos/sangue , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Interferon-alfa/farmacologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos DBA , Modelos Biológicos , Células Mieloides/classificação , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas
8.
Cancer Lett ; 470: 170-180, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31765733

RESUMO

Cyclophosphamide treatment on a medium-dose, intermittent chemotherapy (MEDIC) schedule activates both innate and adaptive immunity leading to major regression of implanted gliomas. Here, we show that this MEDIC treatment regimen induces tumor cell autonomous type-I interferon signaling, followed by release of soluble factors that activate interferon-stimulated genes in both tumor cells and tumor-infiltrating immune cells. In cultured GL261 and CT-2A glioma cells, activated cyclophosphamide stimulated production and release of type-I interferons, leading to robust activation of downstream gene targets. Antibody against the type-I interferon receptor IFNAR1 blocked the cyclophosphamide-stimulated induction of these genes in both cultured glioma cells and implanted gliomas. Furthermore, IFNAR1 antibody strongly inhibited the MEDIC cyclophosphamide-stimulated increases in tumor cell infiltration of macrophages, dendritic cells, B-cells, as well as natural killer cells and cytotoxic T-cells and their cytotoxic effectors. Finally, cyclophosphamide-treated dying glioma cells producing type-I interferons were an effective vaccine against drug-naïve glioma cells implanted in vivo. Thus, cyclophosphamide induces local, tumor cell-centric increases in type-I interferon signaling, which activates immunogenic cell death and is essential for the striking antitumor immune responses that MEDIC cyclophosphamide treatment elicits in these glioma models.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Glioma/tratamento farmacológico , Morte Celular Imunogênica/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Administração Metronômica , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Glioma/imunologia , Glioma/patologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Masculino , Camundongos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Dermatol Sci ; 97(1): 21-29, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31813660

RESUMO

BACKGROUND: The process of repair after skin injury is precisely regulated by a variety of mediators such as cytokines and chemokines. Recent reports demonstrated that cytoplasmic DNA-sensor cyclic GMP-AMP synthase (cGAS) activates the stimulator of interferon genes (STING) via production of cyclic GMP-AMP (cGAMP) and subsequently induces inflammatory cytokines, including type I interferon (IFN). OBJECTIVE: We examined whether activation of the STING pathway by cGAMP affects the process of skin wound repair. METHODS: The skin wound repair model was established using wild-type (WT) mice. Two full-thickness skin biopsies were taken from the right and left subscapular regions. One site was treated with ointment containing cGAMP, and the other was treated with a control ointment. Changes in wound size over time were calculated using photography. RESULTS: Treatment with cGAMP significantly accelerated skin wound healing up to day 6. Biochemical analyses showed that topical treatment with cGAMP on wound sites promoted STING signaling pathway and enhanced the expression of IFN-ß, CXCL10 and CCL2 in the wound sites treated with cGAMP markedly compared with the control. The scratch assay also revealed that cGAMP treatment accelerated wound closure in mouse embryonic fibroblasts. The acceleration of skin wound repair by cGAMP in WT mouse was impaired by administration of anti-IFNR antibody and anti-CXCR3 antibody respectively. CONCLUSION: These results revealed that topical treatment with cGAMP accelerates skin wound healing by inducing type I IFN and CXCL10/CXCR3. Topical administration of cGAMP might contribute to new effective treatments for accelerating skin wound healing.


Assuntos
Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Pele/lesões , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Interferon Tipo I/metabolismo , Masculino , Camundongos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Receptores CXCR3/antagonistas & inibidores , Receptores CXCR3/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Cicatrização/fisiologia
10.
N Engl J Med ; 382(3): 211-221, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31851795

RESUMO

BACKGROUND: Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. METHODS: We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. RESULTS: A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. CONCLUSIONS: Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Receptor de Interferon alfa e beta/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Feminino , Glucocorticoides/uso terapêutico , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
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
12.
J Exp Med ; 216(8): 1791-1808, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164392

RESUMO

Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling safeguards the ability of TCF1hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Autorrenovação Celular/imunologia , Interleucinas/metabolismo , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Memória Imunológica , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Interleucinas/genética , Coriomeningite Linfocítica/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptores CXCR5/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transcriptoma
13.
J Clin Immunol ; 39(5): 476-485, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31144250

RESUMO

OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.


Assuntos
Inibidores de Janus Quinases/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pirazóis/uso terapêutico , Receptor de Interferon alfa e beta/antagonistas & inibidores , Dermatopatias/tratamento farmacológico , Doenças Vasculares/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Interferon Tipo I/sangue , Inibidores de Janus Quinases/efeitos adversos , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/genética , Proteínas de Membrana/genética , Uso Off-Label , Pirazóis/efeitos adversos , Dermatopatias/sangue , Dermatopatias/genética , Síndrome , Resultado do Tratamento , Doenças Vasculares/sangue , Doenças Vasculares/genética
14.
Viruses ; 11(1)2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625992

RESUMO

Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate animal model is a critical concern. Adult mice with gene knockouts of the interferon α/ß (IFN-α/ß) receptor (IFNAR(-/-)) have been described as a model of arbovirus infections. Studies with the natural hosts of these viruses are limited by financial and ethical issues, and in some cases, the need to have facilities with a biosafety level 3 with sufficient space to accommodate large animals. Moreover, the number of animals in the experiments must provide results with statistical significance. Recent advances in animal models in the last decade among other gaps in knowledge have contributed to the better understanding of arbovirus infections. A tremendous advantage of the IFNAR(-/-) mouse model is the availability of a wide variety of reagents that can be used to study many aspects of the immune response to the virus. Although extrapolation of findings in mice to natural hosts must be done with care due to differences in the biology between mouse and humans, experimental infections of IFNAR(-/-) mice with several studied arboviruses closely mimics hallmarks of these viruses in their natural host. Therefore, IFNAR(-/-) mice are a good model to facilitate studies on arbovirus transmission, pathogenesis, virulence, and the protective efficacy of new vaccines. In this review article, the most important arboviruses that have been studied using the IFNAR(-/-) mouse model will be reviewed.


Assuntos
Infecções por Arbovirus/imunologia , Arbovírus/patogenicidade , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Animais , Arbovírus/classificação , Modelos Animais de Doenças , Humanos , Interferon-alfa/imunologia , Interferon beta/imunologia , Camundongos , Camundongos Knockout , Replicação Viral
15.
Nat Commun ; 9(1): 4578, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385785

RESUMO

Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors. However, the impact of microglia depletion and repopulation in the long-term state of the CNS environment has not been characterized. Here, we report that acute and synchronous microglia depletion and subsequent repopulation induces gray matter microgliosis, neuronal death in the somatosensory cortex and ataxia-like behavior. We find a type 1 interferon inflammatory signature in degenerating somatosensory cortex from microglia-depleted mice. Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state. Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type 1 interferon-driven inflammation, restore microglia homeostasis and reduce ataxic behavior. Neither microglia depletion nor repopulation impact neuropathology or T-cell responses during experimental autoimmune encephalomyelitis. Together, we found that acute microglia ablation induces a type 1 interferon activation state of gray matter microglia associated with acute neurodegeneration.


Assuntos
Morte Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Substância Cinzenta/imunologia , Interferon Tipo I/imunologia , Microglia/imunologia , Neurônios/imunologia , Córtex Somatossensorial/imunologia , Animais , Antibacterianos/farmacologia , Ataxia/imunologia , Ataxia/patologia , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Substância Cinzenta/patologia , Homeostase , Imuno-Histoquímica , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Camundongos , Microscopia Confocal , Minociclina/farmacologia , Neurônios/patologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Teste de Desempenho do Rota-Rod , Córtex Somatossensorial/patologia
16.
J Gen Virol ; 99(12): 1671-1680, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30382935

RESUMO

Porcine reproductive and respiratory syndrome (PRRS) is one of the most important diseases in pigs. MicroRNAs (miRNAs) have emerged as an important regulator of virus-host cell interactions and miR-30c has been found to facilitate PRRSV replication. Here, we found that the interferon-alpha/beta receptor beta chain (IFNAR2) was down-regulated, while miR-30c was up-regulated during HV (a highly pathogenic type 2 PRRSV strain) and CH-1a (a classic type 2 PRRSV strain) infection. Subsequently, using bioinformatics analysis, we predicted that the IFNAR2 was targeted by miR-30c. A luciferase assay verified that the 3' UTR of IFNAR2 was targeted by miR-30c, as a mutation on either the target sequence or the miR-30c seed sequence reversed the luciferase activity. In addition, miR-30c and IFNAR2 mRNA were physically co-localized in RNA-induced silencing complex (RISC). Importantly, we showed that miR-30c also impaired the induction of IFN-stimulated genes (ISGs) by targeting IFNAR2. Our findings further reveal the mechanism of miR-30c promoting PRRSV replication.


Assuntos
Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , MicroRNAs/metabolismo , Vírus da Síndrome Respiratória e Reprodutiva Suína/crescimento & desenvolvimento , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Receptor de Interferon alfa e beta/antagonistas & inibidores , Animais , Células Cultivadas , Regulação da Expressão Gênica , Macrófagos Alveolares/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Suínos , Doenças dos Suínos
17.
Nature ; 561(7722): 258-262, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30135585

RESUMO

Although serum from patients with Parkinson's disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1ß, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson's disease2,3. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy4. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson's-disease-relevant phenotypes5-7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8-12, suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn-/- and Pink1-/- mice following exhaustive exercise and in Prkn-/-;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA)13,14. Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA15,16. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn-/-;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.


Assuntos
Imunidade Inata , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Mitofagia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Alarminas/metabolismo , Animais , DNA Mitocondrial/sangue , DNA Mitocondrial/genética , Humanos , Inflamação/genética , Inflamação/prevenção & controle , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/metabolismo , Condicionamento Físico Animal , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Estresse Fisiológico , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética
18.
J Autoimmun ; 94: 7-15, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30115527

RESUMO

IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes. In this review, we dissect the role of IFNα in T1D, focusing on the potential pathophysiological mechanisms involved. Evidence from human and mouse studies indicates that IFNα plays a key role in enhancing islet expression of HLA-I in patients with T1D, thereby increasing autoantigen presentation and beta cell activation of autoreactive cytotoxic CD8 T-lymphocytes. The binding of IFNα to its receptor induces the secretion of chemokines, attracting monocytes, T lymphocytes, and NK cells to the infected tissue triggering autoimmunity in susceptible individuals. Furthermore, IFNα impairs insulin production through the induction of endoplasmic reticulum stress as well as by impairing mitochondrial function. Due to its central role in the early phases of beta cell death, targeting IFNα and its pathways in genetically predisposed individuals may represent a potential novel therapeutic strategy in the very early stages of T1D.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Diabetes Mellitus Tipo 1/imunologia , Regulação da Expressão Gênica/imunologia , Células Secretoras de Insulina/imunologia , Interferon-alfa/imunologia , Receptor de Interferon alfa e beta/imunologia , Animais , Autoantígenos/imunologia , Autoimunidade/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Humanos , Insulina/agonistas , Insulina/biossíntese , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Interferon-alfa/antagonistas & inibidores , Interferon-alfa/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Terapia de Alvo Molecular/métodos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia
19.
Exp Cell Res ; 369(2): 197-207, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29792850

RESUMO

Human cytomegalovirus (HCMV) has led to kinds of clinical disorders and great morbidity worldwide, such as sensorineural hearing loss (SNHL), mental retardation, and developmental delays in immunocompromised individuals. Congenital HCMV infection is a leading cause of birth defects, primarily manifesting as neurological disorders. Previous studies reported that HCMV has evolved a variety of mechanisms to evade the immune system, such as dysregulation of miRNAs. However, reports concerning the role of miRNA in HCMV infection in neural cells are limited. Here, we reported that a host microRNA, miR-182, was significantly up-regulated by HCMV infection in U-251MG and NPCs cells. Subsequently, our results of in vitro and in vivo experiments demonstrated that miR-182 was a positive regulator of interferon regulatory factor 7 (IRF7) by directly targeting FOXO3, resulting in the induction of IFN-I response and suppression of HCMV replication in neural cells. Taken together, our findings provide detailed molecular mechanisms of the antiviral function of miR-182 against HCMV infection in neural cells, and suggest an intrinsic anti-HCMV therapeutic target.


Assuntos
Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Proteína Forkhead Box O3/antagonistas & inibidores , Interferon Tipo I/biossíntese , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Fator Regulador 7 de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neurônios/imunologia , Neurônios/virologia , RNA Interferente Pequeno/genética , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Replicação Viral/genética , Replicação Viral/imunologia , Replicação Viral/fisiologia
20.
J Clin Invest ; 128(6): 2487-2499, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29558366

RESUMO

Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression is the expansion of regulatory T cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type 1 interferon (IFN). Blocking IFN α and ß receptor 1 (IFNAR1) on Tregs significantly decreases both myeloma-associated Treg immunosuppressive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of MM patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type 1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1-knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type 1 IFN signaling represents a potential strategy to target immunosuppressive Treg function in MM.


Assuntos
Proliferação de Células , Tolerância Imunológica , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Receptor de Interferon alfa e beta/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Antineoplásicos/farmacologia , Linhagem Celular , Camundongos , Camundongos Knockout , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/patologia
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