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

项目概要/摘要 Th17细胞通过释放细胞因子来保护宿主免受细胞外细菌的侵害，细胞因子募集并激活细胞因子。 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， 无菌（即无细胞）培养物中的细菌。虽然Th17参与了宿主对 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，我们 研究Th17细胞因子IL-26在由胞内分枝杆菌引起的麻风中的作用 麻风（mLEP），其提供了研究人类对感染的免疫应答的独特模型。疾病 表现为一个谱，其中临床表现与对免疫系统的免疫应答相关。 病原体此外，麻风病的皮肤病变很容易获得进行研究。我们的初步数据 表明IL-26在麻风病皮损中的表达与患者的皮损显著相关， 细菌会随着时间的推移而消失。此外，我们发现IL-26进入mLEP感染的巨噬细胞（M Φ）， 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 生存能力这些数据表明IL-26提供了Th17细胞有助于宿主防御的机制 对抗细胞内细菌因此，我们的总体假设是Th 17细胞的先天激活导致 IL-26的分泌，其有助于宿主防御mLEP和其他细胞内细菌。我们 具体目标是：1）确定细胞外抗微生物蛋白IL-26获得 接触M Φ中的细胞内病原体，导致抗菌反应，2）发现IL-1 β是否通过 Th17细胞的IL-1R+亚群的活化代表了宿主防御细菌感染的先天机制， 感染，以及单核细胞/巨噬细胞在产生IL-26中的作用;和，3）研究IL-26在单核细胞/巨噬细胞中的作用。 26在宿主防御细胞内细菌驻留在不同的亚细胞区室。总之， 拟议的研究将为IL-26促进免疫的机制提供新的见解， 包括IL-26在皮肤感染中的作用。

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.