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

项目摘要/摘要 Th17细胞通过释放细胞因子招募和激活 多种其他类型的细胞，正如我们通过释放能杀死 无菌(即无细胞)培养物中的细菌。尽管Th17被牵连到宿主防御中 胞内细菌的作用机制(S)尚不清楚。由于IL-26存在于人类而不是老鼠体内，我们 Th17细胞因子IL-26在由细胞内分枝杆菌引起的麻风中的作用 麻风(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。这种病 表现为临床表现与免疫反应相关的谱系 病原体。此外，麻风的皮肤病变很容易获得，便于研究。我们的初步数据 提示IL-26在麻风皮损中的表达与麻风患者皮损显著相关。 随着时间的推移，细菌会被消灭。此外，我们还发现IL-26进入mLEP感染的巨噬细胞(MΦS)， 诱导自噬和吞噬溶酶体融合，与细胞内细菌共存并减少其 生存能力。这些数据表明，IL-26提供了一种Th17细胞参与宿主防御的机制 抗细胞内细菌。因此，我们的总体假设是Th17细胞的先天激活导致 分泌IL-26，有助于宿主防御mLEP和其他细胞内细菌。我们的 具体目标是：1)确定一种细胞外抗菌蛋白IL-26获得的机制(S) 接触MΦ中的细胞内病原体S，导致抗微生物反应，2)发现IL-1β，通过 Th17细胞IL-1R亚群的激活，代表了宿主对细菌的天然防御机制 感染以及单核/巨噬细胞在产生IL-26中的作用；以及，3)研究IL-26的作用。 26对寄主防御不同亚细胞室中的胞内细菌。总而言之， 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。

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.