IL-26 in host defense against infection by intracellular bacteria in skin

IL-26 在宿主防御皮肤细胞内细菌感染中的作用

基本信息

批准号：
10402357
负责人：
ROBERT L MODLIN
金额：
$ 40.74万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402357
关键词：
Autophagocytosis Bacillus Bacteria Bacterial Infections Burkholderia Cells Clinical Complex DNA Data Defense Mechanisms Dependence Disease Francisella Genes Host Defense Host Defense Mechanism Human Immune response Immunity Immunobiology Infection Infectious Skin Diseases Interleukin Activation Interleukin-1 beta Interleukin-17 Interleukins Leprosy Lesion Link Listeria Measures Mediating Memory Modeling Mus Mycobacterium leprae Mycobacterium tuberculosis Nucleic Acids Pathogenicity Pathway interactions Patients Pattern recognition receptor Phagosomes Proteins Public Health RNA Reaction Role Salmonella Skin T-Cell Receptor T-Lymphocyte Testing Time Work antimicrobial base cell type combat cytokine defense response extracellular in vivo insight interleukin-10 receptor macrophage monocyte mouse model novel therapeutic intervention pathogen prevent recruit response skin disorder skin lesion

项目摘要

PROJECT SUMMARY/ABSTRACT Th17 cells defend the host against extracellular bacteria by releasing cytokines that recruit and activate a variety of other cell types, and as we discovered by the release of the antimicrobial protein IL-26 that kills bacteria in axenic (i.e. cell-free) cultures. Although Th17 have been implicated in host defense against intracellular bacteria, the mechanism(s) are not known. Because IL-26 is present in humans and not mice, we investigate the role of the Th17 cytokine IL-26 in leprosy, caused by the intracellular bacterium Mycobacterium leprae (mLEP), which provides a unique model to study human immune responses to infection. The disease presents as a spectrum in which the clinical presentation correlates with the immune response to the pathogen. In addition, the skin lesions of leprosy are readily accessible for study. Our preliminary data indicates that IL-26 expression in leprosy lesions significantly correlates with lesions from patients in which bacteria are eliminated over time. In addition, we show that IL-26 enters mLEP-infected macrophages (MΦs), induces autophagy as well as phagolysosomal fusion, colocalizes with the intracellular bacteria and reduces its viability. These data indicate IL-26 provides a mechanism by which Th17 cells contribute to host defense against intracellular bacteria. Our overall hypothesis is therefore that innate activation of Th17 cells leads to secretion of IL-26, which contributes to host defense against mLEP and other intracellular bacteria. Our specific aims are: 1) Determine the mechanism(s) by which an extracellular antimicrobial protein, IL-26 gains access to intracellular pathogens in MΦs, results in an antimicrobial response, 2) Discover if IL-1β, via activation of an IL-1R+ subset of Th17 cells, represents an innate mechanism of host defense against bacterial infection, as well as the role of monocytes/macrophages in producing IL-26; and, 3) Investigate the role of IL- 26 in host defense against intracellular bacteria residing in distinct subcellular compartments. In summary, the proposed studies will provide new insights into the mechanisms by which IL-26 contributes to immunity against intracellular bacteria including the role of IL-26 in skin infection.

项目概要/摘要 Th17 细胞通过释放招募和激活细胞外细菌的细胞因子来保护宿主免受细胞外细菌的侵害。多种其他细胞类型，正如我们通过释放抗菌蛋白 IL-26 发现的那样尽管 Th17 与宿主防御有关，但无菌（即无细胞）培养物中的细菌。细胞内细菌，其机制尚不清楚，因为 IL-26 存在于人类而不是小鼠中。研究 Th17 细胞因子 IL-26 在由细胞内细菌分枝杆菌引起的麻风病中的作用麻风杆菌（mLEP），它提供了一个独特的模型来研究人类对感染的免疫反应。呈现为一个谱系，其中临床表现与对病毒的免疫反应相关此外，我们的初步数据很容易获得麻风病的皮肤损伤。表明麻风病灶中 IL-26 的表达与患者的病灶显着相关此外，我们发现 IL-26 会进入 mLEP 感染的巨噬细胞 (MΦs)，诱导自噬以及吞噬溶酶体融合，与细胞内细菌共定位并减少其这些数据表明 IL-26 提供了 Th17 细胞有助于宿主防御的机制。因此，我们的总体假设是 Th17 细胞的先天激活导致 IL-26 的分泌，有助于宿主防御 mLEP 和其他细胞内细菌。具体目标是： 1) 确定细胞外抗菌蛋白 IL-26 获得的机制接触 MΦs 中的细胞内病原体，导致抗菌反应，2) 发现 IL-1β 是否通过 Th17 细胞 IL-1R+ 子集的激活代表了宿主防御细菌的先天机制感染，以及单核细胞/巨噬细胞在产生 IL-26 中的作用；3) 研究 IL-26 的作用； 26 参与宿主针对不同亚细胞区室中细胞内细菌的防御。拟议的研究将为 IL-26 促进免疫的机制提供新的见解细胞内细菌，包括 IL-26 在皮肤感染中的作用。