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1.
Immunity ; 57(3): 446-461.e7, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38423012

RESUMO

In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.


Assuntos
2',5'-Oligoadenilato Sintetase , Interferons , Oligorribonucleotídeos , Viroses , Febre do Nilo Ocidental , Animais , Humanos , Camundongos , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina , Antivirais/farmacologia , Febre do Nilo Ocidental/genética , Febre do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/patogenicidade
2.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32839612

RESUMO

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Imunidade Inata/imunologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Pneumonia/patologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon Tipo I/imunologia , Interferon gama/imunologia , Queratina-18/genética , Leucócitos/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , NF-kappa B/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/imunologia , Regiões Promotoras Genéticas/genética , SARS-CoV-2 , Linfócitos T/imunologia , Células Vero , Replicação Viral/imunologia
4.
Nature ; 557(7706): 570-574, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29769725

RESUMO

Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease 1 . The host factors required for alphavirus entry remain poorly characterized 2 . Here we use a genome-wide CRISPR-Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O'nyong nyong viruses. Gene editing of mouse Mxra8 or human MXRA8 resulted in reduced levels of viral infection of cells and, reciprocally, ectopic expression of these genes resulted in increased infection. Mxra8 bound directly to chikungunya virus particles and enhanced virus attachment and internalization into cells. Consistent with these findings, Mxra8-Fc fusion protein or anti-Mxra8 monoclonal antibodies blocked chikungunya virus infection in multiple cell types, including primary human synovial fibroblasts, osteoblasts, chondrocytes and skeletal muscle cells. Mutagenesis experiments suggest that Mxra8 binds to a surface-exposed region across the A and B domains of chikungunya virus E2 protein, which are a speculated site of attachment. Finally, administration of the Mxra8-Fc protein or anti-Mxra8 blocking antibodies to mice reduced chikungunya and O'nyong nyong virus infection as well as associated foot swelling. Pharmacological targeting of Mxra8 could form a strategy for mitigating infection and disease by multiple arthritogenic alphaviruses.


Assuntos
Vírus Chikungunya/metabolismo , Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Vírus O'nyong-nyong/metabolismo , Receptores Virais/metabolismo , Células 3T3 , Animais , Anticorpos Bloqueadores/imunologia , Sistemas CRISPR-Cas/genética , Vírus Chikungunya/patogenicidade , Condrócitos/metabolismo , Fibroblastos/metabolismo , Humanos , Imunoglobulinas/imunologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/imunologia , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Vírus O'nyong-nyong/patogenicidade , Osteoblastos/metabolismo , Receptores Fc/metabolismo , Receptores Virais/deficiência , Receptores Virais/genética
5.
J Virol ; 91(22)2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28835505

RESUMO

The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of alpha/beta interferon (IFN-α/ß) (type I), IFN-γ (type II), and IFN-λ (type III). The transcription factor interferon regulatory factor 1 (IRF-1) has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN-stimulated genes (ISGs) and mediating signals downstream of IFN-γ. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role in vivo remains unknown. Here, we infected Irf1 -/- mice with two distantly related arthritogenic alphaviruses, chikungunya virus (CHIKV) and Ross River virus (RRV), and assessed the early antiviral functions of IRF-1 prior to induction of adaptive B and T cell responses. IRF-1 expression limited CHIKV-induced foot swelling in joint-associated tissues and prevented dissemination of CHIKV and RRV at early time points. Virological and histological analyses revealed greater infection of muscle tissues in Irf1 -/- mice than in wild-type mice. The antiviral actions of IRF-1 appeared to be independent of the induction of type I IFN or the effects of type II and III IFNs but were associated with altered local proinflammatory cytokine and chemokine responses and differential infiltration of myeloid cell subsets. Collectively, our in vivo experiments suggest that IRF-1 restricts CHIKV and RRV infection in stromal cells, especially muscle cells, and that this controls local inflammation and joint-associated swelling.IMPORTANCE Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates the expression of a broad range of antiviral host defense genes. In this study, using Irf1 -/- mice, we investigated the role of IRF-1 in modulating pathogenesis of two related arthritogenic alphaviruses, chikungunya virus and Ross River virus. Our studies show that IRF-1 controlled alphavirus replication and swelling in joint-associated tissues within days of infection. Detailed histopathological and virological analyses revealed that IRF-1 preferentially restricted CHIKV infection in cells of nonhematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint-associated tissues, which prevented immunopathology.

6.
J Neuroinflammation ; 13: 22, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26819220

RESUMO

BACKGROUND: Although type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host. METHODS: IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed. RESULTS: We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-ß levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS. CONCLUSIONS: We show that LGTV replication is restricted to the olfactory bulb and that IPS-1 is a very important player in the olfactory bulb in shaping the innate immune response by inhibiting early viral replication and viral spread throughout the central nervous system. In the absence of IPS-1, higher viral replication leads to the evasion of antiviral response by inhibiting interferon signaling. Our data suggest that the local microenvironment of distinct brain regions is critical to determine virus permissiveness.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/patogenicidade , Encefalite Transmitida por Carrapatos/patologia , Interferon Tipo I/metabolismo , Bulbo Olfatório/metabolismo , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antígenos CD , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Regulação Viral da Expressão Gênica/genética , Hipocampo/citologia , Interferon Tipo I/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fatores de Tempo , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
7.
PLoS Pathog ; 10(3): e1003999, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24675692

RESUMO

The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.


Assuntos
Fator Regulador 1 de Interferon/imunologia , Neurônios/virologia , Estomatite Vesicular/imunologia , Replicação Viral/fisiologia , Animais , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Imuno-Histoquímica , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Estomatite Vesicular/metabolismo , Estomatite Vesicular/patologia , Vesiculovirus/fisiologia
8.
J Virol ; 88(21): 12202-12, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25122777

RESUMO

UNLABELLED: Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE: The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/mortalidade , Interferon Tipo I/imunologia , Animais , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/deficiência , Análise de Sobrevida
9.
Gastroenterology ; 145(6): 1414-23.e1, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23973921

RESUMO

BACKGROUND & AIMS: Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication. METHODS: We analyzed replication of the subgenomic JFH1 replicon in embryonic fibroblasts and primary hepatocytes from mice with disruptions in genes encoding factors in the IFN-dependent and alternative antiviral pathways (signal transducers and activators of transcription 1 [STAT1], protein kinase R, interferon regulatory factors (IRF) IRF-1, IRF-3, IRF-5, IRF-7, mitochondrial antiviral signaling molecule [MAVS], and IFN receptor [IFNAR]). We also assessed the effects of expression of these factors by mouse primary hepatocytes on HCV replication. RESULTS: In addition to IRF-3- and IFN-mediated antiviral responses, IFN-independent, but IRF-1- and IRF-5-dependent mechanisms, restrict HCV replication in mouse embryonic fibroblasts. In primary hepatocytes these IFN-independent require MAVS and IRF-1. CONCLUSIONS: HCV replication is limited by interferon-mediated pathways as well pathways that are independent of type I IFNs. IRF1 and IRF5 control IFN-independent signaling events that lead to antiviral responses. We observed antiviral roles of IRF1 and IRF5 that were IFN-independent and cell-type specific. These mechanisms are important in controlling viruses that interfere with the IFN signaling because cells retain the ability to induce functional but local antiviral states through expression of interferon-stimulated genes.


Assuntos
Fibroblastos/virologia , Hepacivirus/fisiologia , Hepatócitos/virologia , Interferons/fisiologia , Transdução de Sinais/fisiologia , Replicação Viral/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Antivirais/uso terapêutico , Fibroblastos/patologia , Hepatite C/tratamento farmacológico , Hepatócitos/patologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/fisiologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/fisiologia
10.
JCI Insight ; 6(1)2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33232299

RESUMO

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with ZIKV, survival increased. ZIKV-mediated tumor clearance also resulted in durable protection against syngeneic tumor rechallenge, which also depended on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which was effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult patients with GBM.


Assuntos
Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/terapia , Inibidores de Checkpoint Imunológico/administração & dosagem , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Zika virus/imunologia , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
11.
bioRxiv ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32676600

RESUMO

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.

12.
J Pediatr Health Care ; 33(3): 296-308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30826137

RESUMO

INTRODUCTION: Asthma is underdiagnosed, particularly for children younger than 5 years old. Clinical practice guidelines have been shown to improve asthma diagnosis and management, but are underutilized. This evidence-based practice project aimed to develop, implement, and evaluate a three-page decision support tool (DST) to improve the asthma diagnosis process among children younger than 5 years old. METHODS: This project used a pre-experimental design and was conducted in a pediatric primary care setting with a predominantly South Asian population. The authors analyzed the utilization of the DST as well as the end-users' perception of the tool. RESULTS: Despite above-average results in the end-users' usability scale, the DST had poor utilization. DISCUSSION: Implementation of the DST is recommended at similar pediatric primary care sites. The EBP Project team recommends translating the DST to the electronic health record and improving the roles of the champion.


Assuntos
Asma/diagnóstico , Sistemas de Apoio a Decisões Clínicas , Padrões de Prática Médica/estatística & dados numéricos , Atenção Primária à Saúde , Pré-Escolar , Registros Eletrônicos de Saúde , Prática Clínica Baseada em Evidências , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Lactente , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde
13.
J Exp Med ; 215(4): 1035-1045, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29511063

RESUMO

Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1-/- mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1-/-, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.


Assuntos
Hidroliases/metabolismo , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Tuberculose/imunologia , Tuberculose/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Progressão da Doença , Feminino , Expressão Gênica/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Succinatos/metabolismo , Transcrição Gênica/imunologia , Tuberculose/microbiologia
14.
Cell Metab ; 24(1): 158-66, 2016 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-27374498

RESUMO

Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1ß-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(-/-) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.


Assuntos
Inflamação/enzimologia , Inflamação/patologia , Macrófagos/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Succinatos/farmacologia , Animais , Respiração Celular/efeitos dos fármacos , Feminino , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Succinato Desidrogenase/metabolismo , Ácido Succínico/metabolismo
15.
Curr Opin Immunol ; 36: 47-53, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26163762

RESUMO

The innate immune system mediates protection against neurotropic viruses that replicate in the central nervous system (CNS). Virus infection within specific cells of the CNS triggers activation of several families of pattern recognition receptors including Toll-like receptors, retinoic acid-inducible gene I like receptors, nucleotide-binding oligomerization domain-like receptors, and cytosolic DNA sensors. In this review, we highlight recent advances in our understanding of how cell-intrinsic host defenses within the CNS modulate infection of different DNA and RNA viruses.


Assuntos
Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/virologia , Interações Hospedeiro-Patógeno , Imunidade Inata , Imunomodulação , Viroses/imunologia , Viroses/virologia , Animais , Viroses do Sistema Nervoso Central/genética , Viroses do Sistema Nervoso Central/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , MicroRNAs/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Viroses/genética , Viroses/metabolismo
16.
Pediatrics ; 111(2): E195-6, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12563096

RESUMO

A 4-week-old boy with previous urinary tract infection and documented vesicoureteral reflux presented with urosepsis and septic arthritis of the right hip. Compliance with prophylactic antibiotic therapy had been poor at home. Complications such as bone and joint infection are known to occur after urinary tract infection in children with urologic abnormalities. However, previous similar reports describe discovery of the urinary tract anomalies only as part of an evaluation performed after the systemic complications have occurred. The purpose of this report is to stress the importance of defining urinary tract abnormalities in a case of antenatal hydronephrosis or at the time of the first urinary tract infection in infants so that appropriate investigations, management, and support of parental compliance can be undertaken to avoid systemic complications.


Assuntos
Artrite Infecciosa/diagnóstico , Infecções Urinárias/diagnóstico , Infecções Urinárias/etiologia , Refluxo Vesicoureteral/complicações , Adulto , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/etiologia , Feminino , Humanos , Recém-Nascido , Infecções por Klebsiella/complicações , Infecções por Klebsiella/diagnóstico , Infecções por Klebsiella/tratamento farmacológico , Masculino , Infecções Urinárias/tratamento farmacológico , Refluxo Vesicoureteral/patologia
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