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1.
Annu Rev Immunol ; 32: 547-77, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24655298

RESUMO

Systems-level analysis of biological processes strives to comprehensively and quantitatively evaluate the interactions between the relevant molecular components over time, thereby enabling development of models that can be employed to ultimately predict behavior. Rapid development in measurement technologies (omics), when combined with the accessible nature of the cellular constituents themselves, is allowing the field of innate immunity to take significant strides toward this lofty goal. In this review, we survey exciting results derived from systems biology analyses of the immune system, ranging from gene regulatory networks to influenza pathogenesis and systems vaccinology.


Assuntos
Imunidade Inata/fisiologia , Biologia de Sistemas , Animais , Controle de Doenças Transmissíveis , Doenças Transmissíveis/etiologia , Humanos , Biologia de Sistemas/métodos , Vacinas/imunologia
2.
Cell ; 183(6): 1479-1495.e20, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171100

RESUMO

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.


Assuntos
COVID-19 , Genômica , RNA-Seq , SARS-CoV-2 , Análise de Célula Única , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Índice de Gravidade de Doença
3.
Nat Immunol ; 20(6): 701-710, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110314

RESUMO

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Caquexia/etiologia , Viroses/complicações , Viroses/imunologia , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia/diagnóstico por imagem , Caquexia/metabolismo , Caquexia/patologia , Doença Crônica , Citocinas/sangue , Citocinas/metabolismo , Feminino , Interferon Tipo I/metabolismo , Metabolismo dos Lipídeos , Lipólise , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Transdução de Sinais , Viroses/virologia
4.
Nat Immunol ; 20(10): 1299-1310, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534238

RESUMO

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.


Assuntos
Infecções por Poxviridae/imunologia , Poxviridae/fisiologia , Domínios Proteicos/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Alelos , Animais , Extinção Biológica , Humanos , Imunidade , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto/genética , Fosforilação
5.
Cell ; 154(1): 213-27, 2013 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23827684

RESUMO

Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation. To elucidate their involvement during influenza infection, liquid chromatography/mass spectrometry lipidomic profiling of 141 lipid species was performed on a mouse influenza model using two viruses of significantly different pathogenicity. Infection by the low-pathogenicity strain X31/H3N2 induced a proinflammatory response followed by a distinct anti-inflammatory response; infection by the high-pathogenicity strain PR8/H1N1 resulted in overlapping pro- and anti-inflammatory states. Integration of the large-scale lipid measurements with targeted gene expression data demonstrated that 5-lipoxygenase metabolites correlated with the pathogenic phase of the infection, whereas 12/15-lipoxygenase metabolites were associated with the resolution phase. Hydroxylated linoleic acid, specifically the ratio of 13- to 9-hydroxyoctadecadienoic acid, was identified as a potential biomarker for immune status during an active infection. Importantly, some of the findings from the animal model were recapitulated in studies of human nasopharyngeal lavages obtained during the 2009-2011 influenza seasons.


Assuntos
Eicosanoides/isolamento & purificação , Ácidos Graxos Insaturados/isolamento & purificação , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/imunologia , Lipídeos/análise , Infecções por Orthomyxoviridae/imunologia , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Eicosanoides/imunologia , Ácidos Graxos Insaturados/imunologia , Humanos , Mediadores da Inflamação/análise , Redes e Vias Metabólicas , Camundongos , Líquido da Lavagem Nasal/imunologia , Transcriptoma
6.
Nat Immunol ; 16(1): 67-74, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25419628

RESUMO

Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-κB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.


Assuntos
Histona-Lisina N-Metiltransferase/imunologia , NF-kappa B/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Pneumonia/imunologia , Superinfecção/imunologia , Animais , Quimiocina CXCL1/imunologia , Suscetibilidade a Doenças , Feminino , Interferon Tipo I/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Infecções por Orthomyxoviridae/enzimologia , Infecções por Orthomyxoviridae/virologia , Pneumonia/enzimologia , Pneumonia/virologia , RNA/química , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Organismos Livres de Patógenos Específicos , Superinfecção/enzimologia , Superinfecção/microbiologia
7.
Proc Natl Acad Sci U S A ; 121(33): e2406492121, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39361877

RESUMO

Toll-like receptors (TLRs) on macrophages sense microbial components and trigger the production of numerous cytokines and chemokines that mediate the inflammatory response to infection. Although many of the components required for the activation of the TLR pathway have been identified, the mechanisms that appropriately regulate the magnitude and duration of the response and ultimately restore homeostasis are less well understood. Furthermore, a growing body of work indicates that TLR signaling reciprocally interacts with other fundamental cellular processes, including lipid metabolism but only a few specific molecular links between immune signaling and the macrophage lipidome have been studied in detail. Oxysterol-binding protein (Osbp) is the founding member of a family of lipid-binding proteins with diverse functions in lipid sensing, lipid transport, and cell signaling but its role in TLR responses is not well defined. Here, we demonstrate that altering the state of Osbp with its natural ligand, 25-hydroxycholesterol (25HC), or pharmacologically, sustains and thereby amplifies Tlr4-induced cytokine production in vitro and in vivo. CRISPR-induced knockdown of Osbp abrogates the ability of these ligands to sustain TLR responses. Lipidomic analysis suggested that the effect of Osbp on TLR signaling may be mediated by alterations in triglyceride production and treating cells with a Dgat1 inhibitor, which blocks triglyceride production and completely abrogates the effect of Osbp on TLR signaling. Thus, Osbp is a sterol sensor that transduces perturbations of the lipidome to modulate the resolution of macrophage inflammatory responses.


Assuntos
Citocinas , Hidroxicolesteróis , Macrófagos , Receptores de Esteroides , Transdução de Sinais , Animais , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos , Citocinas/metabolismo , Receptores de Esteroides/metabolismo , Receptores de Esteroides/genética , Hidroxicolesteróis/metabolismo , Receptores Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos , Células RAW 264.7
8.
PLoS Pathog ; 20(1): e1011871, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38236787

RESUMO

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Camundongos , Animais , Macrófagos Alveolares , Lipopolissacarídeos , Interferons
9.
Nat Immunol ; 13(7): 659-66, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22610141

RESUMO

Although the mechanisms by which innate pathogen-recognition receptors enhance adaptive immune responses are increasingly well understood, whether signaling events from distinct classes of receptors affect each other in modulating adaptive immunity remains unclear. We found here that the activation of cytosolic RIG-I-like receptors (RLRs) resulted in the selective suppression of transcription of the gene encoding the p40 subunit of interleukin 12 (Il12b) that was effectively induced by the activation of Toll-like receptors (TLRs). The RLR-activated transcription factor IRF3 bound dominantly, relative to IRF5, to the Il12b promoter, where it interfered with the TLR-induced assembly of a productive transcription-factor complex. The activation of RLRs in mice attenuated TLR-induced responses of the T helper type 1 cell (T(H)1 cell) and interleukin 17-producing helper T cell (T(H)17 cell) subset types and, consequently, viral infection of mice caused death at sublethal doses of bacterial infection. The innate immune receptor cross-interference we describe may have implications for infection-associated clinical episodes.


Assuntos
Transdução de Sinais/imunologia , Linfócitos T/imunologia , Receptores Toll-Like/imunologia , Sequência de Aminoácidos , Animais , Infecções Bacterianas/imunologia , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Fator Regulador 3 de Interferon/metabolismo , Fatores Reguladores de Interferon/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Células Th1/imunologia , Células Th17/imunologia , Fatores de Transcrição/metabolismo , Viroses/imunologia
10.
Immunity ; 43(5): 974-86, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26588782

RESUMO

Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.


Assuntos
Hepatócitos/imunologia , Interferon Tipo I/imunologia , Estresse Oxidativo/imunologia , Superóxido Dismutase/imunologia , Animais , Antioxidantes/metabolismo , Hepatite Viral Animal/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Transdução de Sinais/imunologia , Superóxido Dismutase-1 , Linfócitos T/imunologia , Transcrição Gênica/imunologia
11.
Immunity ; 42(4): 679-91, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25902482

RESUMO

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.


Assuntos
Ilhas de CpG/imunologia , Epigênese Genética , Macrófagos Peritoneais/imunologia , Proteína 2 de Ligação a Metil-CpG/imunologia , Microglia/imunologia , Síndrome de Rett/imunologia , Animais , Receptor 1 de Quimiocina CX3C , Metilação de DNA , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Homeostase/imunologia , Humanos , Integrases/genética , Integrases/imunologia , Longevidade/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/deficiência , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/patologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Síndrome de Rett/genética , Síndrome de Rett/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia
12.
Nat Immunol ; 12(8): 786-95, 2011 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-21743478

RESUMO

Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.


Assuntos
Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Orthomyxoviridae/imunologia , Imunidade Adaptativa/imunologia , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , Perfilação da Expressão Gênica , Testes de Inibição da Hemaglutinação , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estações do Ano , Biologia de Sistemas/métodos , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Adulto Jovem
13.
J Immunol ; 206(12): 2949-2965, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34031149

RESUMO

APCs such as myeloid dendritic cells (DCs) are key sentinels of the innate immune system. In response to pathogen recognition and innate immune stimulation, DCs transition from an immature to a mature state that is characterized by widespread changes in host gene expression, which include the upregulation of cytokines, chemokines, and costimulatory factors to protect against infection. Several transcription factors are known to drive these gene expression changes, but the mechanisms that negatively regulate DC maturation are less well understood. In this study, we identify the transcription factor IL enhancer binding factor 3 (ILF3) as a negative regulator of innate immune responses and DC maturation. Depletion of ILF3 in primary human monocyte-derived DCs led to increased expression of maturation markers and potentiated innate responses during stimulation with viral mimetics or classic innate agonists. Conversely, overexpression of short or long ILF3 isoforms (NF90 and NF110) suppressed DC maturation and innate immune responses. Through mutagenesis experiments, we found that a nuclear localization sequence in ILF3, and not its dual dsRNA-binding domains, was required for this function. Mutation of the domain associated with zinc finger motif of ILF3's NF110 isoform blocked its ability to suppress DC maturation. Moreover, RNA-sequencing analysis indicated that ILF3 regulates genes associated with cholesterol homeostasis in addition to genes associated with DC maturation. Together, our data establish ILF3 as a transcriptional regulator that restrains DC maturation and limits innate immune responses through a mechanism that may intersect with lipid metabolism.


Assuntos
Células Dendríticas , Transdução de Sinais , Humanos , Imunidade Inata , Monócitos , Isoformas de Proteínas/genética
14.
Proc Natl Acad Sci U S A ; 117(27): 15789-15798, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581129

RESUMO

Patients infected with influenza are at high risk of secondary bacterial infection, which is a major proximate cause of morbidity and mortality. We have shown that in mice, prior infection with influenza results in increased inflammation and mortality upon Staphylococcus aureus infection, recapitulating the human disease. Lipidomic profiling of the lungs of superinfected mice revealed an increase in CYP450 metabolites during lethal superinfection. These lipids are endogenous ligands for the nuclear receptor PPARα, and we demonstrate that Ppara-/- mice are less susceptible to superinfection than wild-type mice. PPARα is an inhibitor of NFκB activation, and transcriptional profiling of cells isolated by bronchoalveolar lavage confirmed that influenza infection inhibits NFκB, thereby dampening proinflammatory and prosurvival signals. Furthermore, network analysis indicated an increase in necrotic cell death in the lungs of superinfected mice compared to mice infected with S. aureus alone. Consistent with this, we observed reduced NFκB-mediated inflammation and cell survival signaling in cells isolated from the lungs of superinfected mice. The kinase RIPK3 is required to induce necrotic cell death and is strongly induced in cells isolated from the lungs of superinfected mice compared to mice infected with S. aureus alone. Genetic and pharmacological perturbations demonstrated that PPARα mediates RIPK3-dependent necroptosis and that this pathway plays a central role in mortality following superinfection. Thus, we have identified a molecular circuit in which infection with influenza induces CYP450 metabolites that activate PPARα, leading to increased necrotic cell death in the lung which correlates with the excess mortality observed in superinfection.


Assuntos
Inflamação/genética , Influenza Humana/genética , PPAR alfa/genética , Infecções Estafilocócicas/genética , Superinfecção/genética , Animais , Lavagem Broncoalveolar/métodos , Coinfecção/genética , Coinfecção/microbiologia , Coinfecção/mortalidade , Sistema Enzimático do Citocromo P-450/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Inflamação/microbiologia , Inflamação/mortalidade , Influenza Humana/microbiologia , Influenza Humana/mortalidade , Pulmão/microbiologia , Pulmão/patologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Knockout , Necroptose/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Superinfecção/mortalidade
15.
J Infect Dis ; 225(10): 1832-1840, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-33693706

RESUMO

Previous studies have identified whole-blood transcriptional risk and disease signatures for tuberculosis; however, several lines of evidence suggest that these signatures primarily reflect bacterial burden, which increases before symptomatic disease. We found that the peripheral blood transcriptome of mice with contained Mycobacterium tuberculosis infection (CMTI) has striking similarities to that of humans with active tuberculosis and that a signature derived from these mice predicts human disease with accuracy comparable to that of signatures derived directly from humans. A set of genes associated with immune defense are up-regulated in mice with CMTI but not in humans with active tuberculosis, suggesting that their up-regulation is associated with bacterial containment. A signature comprising these genes predicts both protection from tuberculosis disease and successful treatment at early time points where current signatures are not predictive. These results suggest that detailed study of the CMTI model may enable identification of biomarkers for human tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Biomarcadores , Humanos , Camundongos , Transcriptoma
16.
PLoS Pathog ; 16(7): e1008655, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673357

RESUMO

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.


Assuntos
Modelos Animais de Doenças , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/virologia , Animais , Macrófagos Alveolares/imunologia , Camundongos
17.
Nat Immunol ; 11(12): 1136-42, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21057511

RESUMO

Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1ß (IL-1ß) and IL-18. Although infection with wild-type Salmonella typhimurium is lethal to mice, we show here that a strain that persistently expresses flagellin was cleared by the cytosolic flagellin-detection pathway through the activation of caspase-1 by the NLRC4 inflammasome; however, this clearance was independent of IL-1ß and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1ß and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.


Assuntos
Apoptose/imunologia , Caspase 1/imunologia , Imunidade Inata/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imuno-Histoquímica , Inflamassomos/imunologia , Inflamassomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL
18.
Nat Immunol ; 10(4): 437-43, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19270711

RESUMO

The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems-biology approaches to predict and confirm the existence of a gene-regulatory network involving dynamic interaction among the transcription factors NF-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPdelta and experimentally confirmed the prediction that the combination of an initiator (NF-kappaB), an amplifier (C/EBPdelta) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.


Assuntos
Fator 3 Ativador da Transcrição/imunologia , Células da Medula Óssea/imunologia , Proteína delta de Ligação ao Facilitador CCAAT/imunologia , Macrófagos/imunologia , Biologia de Sistemas , Receptor 4 Toll-Like/imunologia , Fator 3 Ativador da Transcrição/fisiologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/fisiologia , Células Cultivadas , Infecções por Escherichia coli/imunologia , Redes Reguladoras de Genes , Imunidade Inata , Interleucina-6/imunologia , Interleucina-6/fisiologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Genéticos , NF-kappa B/imunologia , NF-kappa B/fisiologia , Receptor 4 Toll-Like/fisiologia
19.
Nat Immunol ; 10(1): 116-125, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19029902

RESUMO

A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.


Assuntos
Perfilação da Expressão Gênica/métodos , Imunidade Inata/genética , Biologia de Sistemas/métodos , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/genética , Células Cultivadas , Ensaios Clínicos Controlados como Assunto , Humanos , Imunidade Ativa/genética , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Análise Multivariada , Testes de Neutralização , Proteínas Serina-Treonina Quinases/genética , Fator de Necrose Tumoral alfa/genética , Vacinação , Vacina contra Febre Amarela/uso terapêutico , Adulto Jovem
20.
Mol Syst Biol ; 15(3): e8584, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833303

RESUMO

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA Using Path-seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/desA2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Adaptação Fisiológica , Animais , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Parede Celular/metabolismo , Macrófagos/microbiologia , Camundongos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/metabolismo , Biologia de Sistemas , Tuberculose/imunologia
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