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1.
J Clin Invest ; 129(5): 1926-1939, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30939123

RESUMO

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Furthermore, IL-26, when added to human monocyte-derived macrophages infected with M. leprae, entered the infected cell, colocalized with the bacterium, and reduced bacteria viability. In addition, IL-26 induced autophagy via the cytoplasmic DNA receptor stimulator of IFN genes (STING), as well as fusion of phagosomes containing bacilli with lysosomal compartments. Altogether, our data suggest that the Th17 cytokine IL-26 contributes to host defense against intracellular bacteria.


Assuntos
Interleucinas/imunologia , Hanseníase Virchowiana/microbiologia , Hanseníase Tuberculoide/microbiologia , Células Th17/imunologia , Autofagia , Citocinas/imunologia , Perfilação da Expressão Gênica , Humanos , Lisossomos/imunologia , Lisossomos/microbiologia , Macrófagos/imunologia , Monócitos/citologia , Mycobacterium leprae , Mycobacterium tuberculosis , Fagossomos/imunologia , Proteínas Recombinantes/imunologia , Transdução de Sinais
2.
JCI Insight ; 4(8)2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30996142

RESUMO

DC, through the uptake, processing, and presentation of antigen, are responsible for activation of T cell responses to defend the host against infection, yet it is not known if they can directly kill invading bacteria. Here, we studied in human leprosy, how Langerhans cells (LC), specialized DC, contribute to host defense against bacterial infection. IFN-γ treatment of LC isolated from human epidermis and infected with Mycobacterium leprae (M. leprae) activated an antimicrobial activity, which was dependent on the upregulation of the antimicrobial peptide cathelicidin and induction of autophagy. IFN-γ induction of autophagy promoted fusion of phagosomes containing M. leprae with lysosomes and the delivery of cathelicidin to the intracellular compartment containing the pathogen. Autophagy enhanced the ability of M. leprae-infected LC to present antigen to CD1a-restricted T cells. The frequency of IFN-γ labeling and LC containing both cathelicidin and autophagic vesicles was greater in the self-healing lesions vs. progressive lesions, thus correlating with the effectiveness of host defense against the pathogen. These data indicate that autophagy links the ability of DC to kill and degrade an invading pathogen, ensuring cell survival from the infection while facilitating presentation of microbial antigens to resident T cells.


Assuntos
Apresentação de Antígeno , Autofagia , Células de Langerhans/imunologia , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Antígenos de Bactérias/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Autofagossomos/imunologia , Autofagossomos/metabolismo , Autofagossomos/microbiologia , Biópsia , Células Cultivadas , Epiderme/imunologia , Epiderme/microbiologia , Epiderme/patologia , Humanos , Interferon gama/imunologia , Células de Langerhans/microbiologia , Células de Langerhans/ultraestrutura , Hanseníase/microbiologia , Hanseníase/patologia , Lisossomos/imunologia , Lisossomos/metabolismo , Lisossomos/microbiologia , Microscopia Eletrônica de Transmissão , Mycobacterium leprae/isolamento & purificação , Cultura Primária de Células , Proteínas Recombinantes/imunologia , Linfócitos T/imunologia , Regulação para Cima/imunologia , Catelicidinas
3.
PLoS Pathog ; 12(6): e1005705, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27355424

RESUMO

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.


Assuntos
Hanseníase/imunologia , Macrófagos/imunologia , Proteína S100A12/imunologia , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Macrófagos/microbiologia , Infecções por Mycobacterium/imunologia , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
4.
Cancer Res ; 73(14): 4222-32, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23860718

RESUMO

Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress.


Assuntos
Inflamação/microbiologia , Intestinos/microbiologia , Lactobacillus/fisiologia , Leucócitos/microbiologia , Linfoma de Células B/metabolismo , Linfoma de Células B/microbiologia , Animais , Ataxia Telangiectasia/complicações , Instabilidade Genômica , Incidência , Linfoma de Células B/genética , Masculino , Camundongos , Camundongos Transgênicos , Microbiota , Estresse Oxidativo/fisiologia
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