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2.
Nat Immunol ; 25(3): 418-431, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38225437

RESUMO

After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αß T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.


Assuntos
Vacina BCG , Vírus da Influenza A , Infecções por Orthomyxoviridae , Animais , Camundongos , Administração Intravenosa , Vacina BCG/imunologia , Células T de Memória , Imunidade Treinada , Vacinação , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle
3.
Immunity ; 56(7): 1502-1514.e8, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37160117

RESUMO

Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.


Assuntos
Esclerose Múltipla , Animais , Humanos , Camundongos , Sistema Nervoso Central , Interleucina-3 , Microglia , Neuroglia/metabolismo
4.
Immunity ; 56(4): 783-796.e7, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-36827982

RESUMO

Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear. Here, we identified a fasting-induced switch in leukocyte migration that prolongs monocyte lifespan and alters susceptibility to disease in mice. We show that fasting during the active phase induced the rapid return of monocytes from the blood to the bone marrow. Monocyte re-entry was orchestrated by hypothalamic-pituitary-adrenal (HPA) axis-dependent release of corticosterone, which augmented the CXCR4 chemokine receptor. Although the marrow is a safe haven for monocytes during nutrient scarcity, re-feeding prompted mobilization culminating in monocytosis of chronologically older and transcriptionally distinct monocytes. These shifts altered response to infection. Our study shows that diet-in particular, a diet's temporal dynamic balance-modulates monocyte lifespan with consequences for adaptation to external stressors.


Assuntos
Medula Óssea , Monócitos , Camundongos , Animais , Células da Medula Óssea , Jejum , Quimiocinas/metabolismo
5.
J Exp Med ; 219(11)2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36129517

RESUMO

A sleepless night may feel awful in its aftermath, but sleep's revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal diversity through accelerated genetic drift. Sleep fragmentation exerts a lasting influence on the HSPC epigenome, skewing commitment toward a myeloid fate and priming cells for exaggerated inflammatory bursts. Combining hematopoietic clonal tracking with mathematical modeling, we infer that sleep preserves clonal diversity by limiting neutral drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis. These findings show that sleep slows decay of the hematopoietic system by calibrating the hematopoietic epigenome, constraining inflammatory output, and maintaining clonal diversity.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Células Cultivadas , Hematopoese/genética , Células-Tronco Hematopoéticas/fisiologia , Humanos , Sono/genética
6.
Cell Rep ; 39(12): 110974, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732121

RESUMO

Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD-/- mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD-/- NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD-/- mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.


Assuntos
Vírus da Influenza A , Influenza Humana , Mitocôndrias , Infecções por Orthomyxoviridae , Animais , Peptidil-Prolil Isomerase F , Humanos , Interleucinas , Células Matadoras Naturais , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Interleucina 22
7.
Nature ; 607(7919): 578-584, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35636458

RESUMO

The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.


Assuntos
Encéfalo , Medo , Leucócitos , Neurônios Motores , Vias Neurais , Estresse Psicológico , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Encéfalo/citologia , Encéfalo/fisiologia , COVID-19/imunologia , Quimiocinas/imunologia , Suscetibilidade a Doenças , Medo/fisiologia , Glucocorticoides/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia , Neurônios Motores/citologia , Neurônios Motores/fisiologia , Neutrófilos/citologia , Neutrófilos/imunologia , Optogenética , Infecções por Orthomyxoviridae/imunologia , Núcleo Hipotalâmico Paraventricular/fisiologia , SARS-CoV-2/imunologia , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia
9.
Front Immunol ; 13: 1044592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36776396

RESUMO

Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a virulent strain of Mycobacterium tuberculosis (H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for Mtb survival and that metabolic reprogramming may be a viable host targeted therapy against TB.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Macrófagos Alveolares/metabolismo , Tuberculose/microbiologia , Macrófagos/microbiologia , Necrose/metabolismo
10.
Nature ; 595(7869): 701-706, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34262178

RESUMO

Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of ß-amyloid (Aß) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aß deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aß and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/fisiologia , Interleucina-3/metabolismo , Microglia/fisiologia , Animais , Comunicação Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/fisiologia
11.
Cell ; 183(3): 752-770.e22, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33125891

RESUMO

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.


Assuntos
Células-Tronco Hematopoéticas/microbiologia , Imunidade , Mycobacterium tuberculosis/fisiologia , Mielopoese , Animais , Células da Medula Óssea/metabolismo , Proliferação de Células , Suscetibilidade a Doenças , Homeostase , Interferon Tipo I/metabolismo , Ferro/metabolismo , Cinética , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Necrose , Transdução de Sinais , Transcrição Gênica , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/patologia
12.
Immunohorizons ; 4(4): 217-230, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332052

RESUMO

CD8+ T cell-mediated immunity is critical for host defense against viruses and requires mitochondria-mediated type I IFN (IFN-I) signaling for optimal protection. Cyclophilin D (CypD) is a mitochondrial matrix protein that modulates the mitochondrial permeability transition pore, but its role in IFN-I signaling and CD8+ T cell responses to viral infection has not been previously explored. In this study, we demonstrate that CypD plays a critical extrinsic role in the survival of Ag-specific CD8+ T cell following acute viral infection with lymphocytic choriomeningitis virus in mice. CypD deficiency resulted in reduced IFN-I and increased CD8+ T cell death, resulting in a reduced antiviral CD8+ T cell response. In addition, CypD deficiency was associated with an increase in pathogen burden at an early time-point following infection. Furthermore, our data demonstrate that transfer of wild-type macrophages (expressing CypD) to CypD-deficient mice can partially restore CD8+ T cell responses. These results establish that CypD plays an extrinsic role in regulating optimal effector CD8+ T cell responses to viral infection. Furthermore, this suggests that, under certain circumstances, inhibition of CypD function may have a detrimental impact on the host's ability to respond to viral infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular/genética , Interações entre Hospedeiro e Microrganismos/genética , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Peptidil-Prolil Isomerase F/metabolismo , Transferência Adotiva/métodos , Animais , Antígenos CD8/metabolismo , Peptidil-Prolil Isomerase F/genética , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Coriomeningite Linfocítica/terapia , Coriomeningite Linfocítica/virologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/genética
14.
Sci Rep ; 9(1): 17620, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772273

RESUMO

Inactivation of the protein complex 'mechanistic target of rapamycin complex 1' (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including 'protein kinase C delta' (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional 'target of rapamycin signaling' (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-ß. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-ß, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.


Assuntos
Núcleo Celular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína Quinase C-delta/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Motivos de Aminoácidos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular , Humanos , Modelos Moleculares , Mutação de Sentido Incorreto , Mutação Puntual , Conformação Proteica , Mapeamento de Interação de Proteínas , Proteína Quinase C-delta/química , Proteína Quinase C-delta/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Fator de Transcrição STAT1/biossíntese , Alinhamento de Sequência , Sirolimo/farmacologia , alfa Carioferinas/antagonistas & inibidores , alfa Carioferinas/metabolismo
15.
J Allergy Clin Immunol ; 144(4): 945-961.e9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31356919

RESUMO

BACKGROUND: Inhaled oxidative toxicants present in ambient air cause airway epithelial injury, inflammation, and airway hyperresponsiveness. Effective adaptation to such environmental insults is essential for the preservation of pulmonary function, whereas failure or incomplete adaptation to oxidative injury can render the host susceptible to the development of airway disease. OBJECTIVE: We sought to explore the mechanisms of airway adaptation to oxidative injury. METHODS: For a model to study pulmonary adaptation to oxidative stress-induced lung injury, we exposed mice to repeated nose-only chlorine gas exposures. Outcome measures were evaluated 24 hours after the last chlorine exposure. Lung mechanics and airway responsiveness to methacholine were assessed by using the flexiVent. Inflammation and antioxidant responses were assessed in both bronchoalveolar lavage fluid and lung tissue. Using both loss or gain of function and genomic approaches, we further dissected the cellular and molecular mechanisms involved in pulmonary adaptation. RESULTS: Repeated exposures to oxidative stress resulted in pulmonary adaptation evidenced by abrogation of neutrophilic inflammation and airway hyperresponsiveness. This adaptation was independent of antioxidant mechanisms and regulatory T cells but dependent on residential alveolar macrophages (AMs). Interestingly, 5% of AMs expressed forkhead box P3, and depletion of these cells abolished adaptation. Results from transcriptomic profiling and loss and gain of function suggest that adaptation might be dependent on TGF-ß and prostaglandin E2. CONCLUSION: Pulmonary adaptation during oxidative stress-induced lung injury is mediated by a novel subset of forkhead box P3-positive AMs that limits inflammation, favoring airway adaptation and host fitness through TGF-ß and prostaglandin E2.


Assuntos
Adaptação Fisiológica/fisiologia , Macrófagos Alveolares/metabolismo , Estresse Oxidativo/imunologia , Hipersensibilidade Respiratória/metabolismo , Animais , Cloro/toxicidade , Dinoprostona/metabolismo , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Irritantes/toxicidade , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/imunologia , Fator de Crescimento Transformador beta/metabolismo
16.
Science ; 365(6448)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31273097

RESUMO

Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.


Assuntos
Citosol/enzimologia , Citosol/imunologia , Imunidade Inata , Proteínas Serina-Treonina Quinases/fisiologia , Resposta a Proteínas não Dobradas/imunologia , Fator 4 Ativador da Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Linhagem Celular , Chaperona BiP do Retículo Endoplasmático , Fator de Iniciação 2 em Eucariotos/metabolismo , Fibroblastos , Proteínas de Choque Térmico/metabolismo , Humanos , Listeria/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Chaperonas Moleculares/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Adaptadora de Sinalização NOD1/química , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteínas Serina-Treonina Quinases/genética , Salmonella/imunologia , Infecções por Salmonella , Shigella/imunologia , Transdução de Sinais
17.
Nat Microbiol ; 4(8): 1389-1400, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31110361

RESUMO

Host defence against influenza A virus (IAV) infection depends not only on host resistance to eliminate the virus, but also disease tolerance to limit lung tissue damage and maintain pulmonary function. Fatal IAV infections are frequently the result of a maladaptive immune response that compromises disease tolerance rather than host resistance to infection. Here, we show that the leukotriene B4 (LTB4)-type I interferon (IFN) axis promotes a distinct mechanism of disease tolerance to pulmonary IAV infection. We demonstrate that mice genetically deficient in LTB4 signalling (Blt1R-/-) are more susceptible to IAV infection compared to control mice, despite similar pulmonary viral loads. The increased susceptibility of Blt1R-/- mice is associated with an accumulation of inflammatory monocyte-derived macrophages (IMMs) causing increased lung immunopathology. We mechanistically define that LTB4 signalling via the BLT1 receptor enhances the activation of the type I IFN-α/ß receptor (IFNAR)/ and signal transducer and activator of transcription 1 (STAT1), which leads to IFN-α production by interstitial macrophages to suppresse in situ IMM proliferation. Importantly, the delivery of a single dose of LTB4 at the peak viral load reduces IMM proliferation, controls tissue damage and increases survival without affecting host resistance to IAV. These results reveal an unexpected anti-inflammatory role of LTB4 in disease tolerance to IAV infection.


Assuntos
Tolerância Imunológica , Imunidade Inata/imunologia , Influenza Humana/imunologia , Interferon Tipo I/metabolismo , Leucotrieno B4/metabolismo , Macrófagos/metabolismo , Animais , Morte Celular , Linhagem Celular , Proliferação de Células , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores CCR2/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
18.
Microbes Infect ; 20(9-10): 560-569, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29679740

RESUMO

Influenza A virus (IAV) is a pulmonary pathogen, responsible for significant yearly morbidity and mortality. Due to the absence of highly effective antiviral therapies and vaccine, as well as the constant threat of an emerging pandemic strain, there is considerable need to better understand the host-pathogen interactions and the factors that dictate a protective versus detrimental immune response to IAV. Even though evidence of IAV-induced cell death in human pulmonary epithelial and immune cells has been observed for almost a century, very little is known about the consequences of cell death on viral pathogenesis. Recent study indicates that both the type of cell death program and its kinetics have major implications on host defense and survival. In this review, we discuss advances in our understanding of cell death programs during influenza virus infection, in hopes of fostering new areas of investigation for targeted clinical intervention.


Assuntos
Morte Celular , Interações Hospedeiro-Patógeno/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Células Epiteliais Alveolares/patologia , Animais , Humanos , Cinética , Macrófagos Alveolares/patologia , Infecções por Orthomyxoviridae/imunologia
19.
PLoS Pathog ; 13(4): e1006326, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28410401

RESUMO

The type I interferon pathway plays a critical role in both host defense and tolerance against viral infection and thus requires refined regulatory mechanisms. RIPK3-mediated necroptosis has been shown to be involved in anti-viral immunity. However, the exact role of RIPK3 in immunity to Influenza A Virus (IAV) is poorly understood. In line with others, we, herein, show that Ripk3-/- mice are highly susceptible to IAV infection, exhibiting elevated pulmonary viral load and heightened morbidity and mortality. Unexpectedly, this susceptibility was linked to an inability of RIKP3-deficient macrophages (Mφ) to produce type I IFN in the lungs of infected mice. In Mφ infected with IAV in vitro, we found that RIPK3 regulates type I IFN both transcriptionally, by interacting with MAVS and limiting RIPK1 interaction with MAVS, and post-transcriptionally, by activating protein kinase R (PKR)-a critical regulator of IFN-ß mRNA stability. Collectively, our findings indicate a novel role for RIPK3 in regulating Mφ-mediated type I IFN anti-viral immunity, independent of its conventional role in necroptosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Interferon beta/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Humanos , Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Interferon beta/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
20.
Cell Tissue Res ; 367(3): 525-536, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28168323

RESUMO

The appearance of single cell microorganisms on earth dates back to more than 3.5 billion years ago, ultimately leading to the development of multicellular organisms approximately 3 billion years later. The evolutionary burst of species diversity and the "struggle for existence", as proposed by Darwin, generated a complex host defense system. Host survival during infection in vital organs, such as the lung, requires a delicate balance between host defense, which is essential for the detection and elimination of pathogens and host tolerance, which is critical for minimizing collateral tissue damage. Whereas the cellular and molecular mechanisms of host defense against many invading pathogens have been extensively studied, our understanding of host tolerance as a key mechanism in maintaining host fitness is extremely limited. This may also explain why current therapeutic and preventive approaches targeting only host defense mechanisms have failed to provide full protection against severe infectious diseases, including pulmonary influenza virus and Mycobacterium tuberculosis infections. In this review, we aim to outline various host strategies of resistance and tolerance for effective protection against acute or chronic pulmonary infections.


Assuntos
Doenças Transmissíveis/imunologia , Resistência à Doença/imunologia , Interações Hospedeiro-Patógeno/imunologia , Tolerância Imunológica , Pneumopatias/imunologia , Humanos
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