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

• 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
• 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

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.

项目摘要/摘要 Th17细胞通过释放募集和激活A的细胞因子来捍卫宿主免受细胞外细菌的影响 其他各种细胞类型，正如我们通过释放抗菌蛋白IL-26杀死发现的那样 轴原（即无细胞）培养物中的细菌。虽然在托管防御中暗示了TH17 细胞内细菌，机制尚不清楚。因为IL-26存在于人类而不是老鼠中，所以我们 研究Th17细胞因子IL-26在麻风病中的作用，这是由细胞内细菌菌群引起的 Leprae（MLEP），它提供了一种独特的模型来研究人类免疫调查的感染。疾病 作为临床表现与免疫反应相关的频谱 病原。此外，麻风病的皮肤病变很容易进行研究。我们的初步数据 表明麻风病变中的IL-26表达与患者的病变显着相关 随着时间的流逝，细菌被消除。此外，我们表明IL-26进入MLEP感染的巨噬细胞（MφS）， 诱导自噬和吞噬物质融合，与细胞内细菌共定位并减少其 生存能力。这些指示IL-26的数据提供了一种机制，Th17细胞有助于宿主防御 针对细胞内细菌。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，有助于宿主对MLEP和其他细胞内细菌的防御。我们的 具体目的是：1）确定细胞外抗菌蛋白IL-26增长的机制 在MφS中获得细胞内病原体的访问，导致抗菌反应，2）发现IL-1β是否是否通过 Th17细胞的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-的作用 26在宿主防御侵害不同细胞室内的细胞内细菌中。总而言之， 拟议的研究将为IL-26有助于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。