Immunopathology of early and subclinical Mycobacterium avium subspecies paratuberculosis infection in calves

这项研究旨在提高我们对宿主天然免疫和对分枝杆菌感染的抵抗力的了解。我感兴趣的是宿主先天免疫细胞和入侵的分枝杆菌之间的相互作用如何影响感染的结果。禽类分支杆菌副结核亚种(MAP)引起约翰氏病，这是一种影响加拿大和世界各地肉牛和奶牛的重要且代价高昂的肠道疾病。包括MAP在内的控制分枝杆菌感染的全球努力取得了有限的成功，这在很大程度上是因为导致宿主免疫成功(消除感染)或失败(建立持续感染)的基本机制尚不清楚。γ-增量T淋巴细胞是一类独特的天然免疫细胞，最近被认为是宿主防御的协调者，它通过引导获得性免疫而被认为是清除入侵分枝杆菌所必需的。我们已经观察到在小牛的感染部位招募了γ-增量T细胞，但是关于它们在宿主免疫中的作用的机制还没有被阐明。在这些研究中，我们将研究这些天然细胞如何在MAP初始感染期间引导宿主免疫：1)它们如何被招募到早期感染部位；2)它们如何影响其他免疫细胞(巨噬细胞、树突状细胞)的功能，这些细胞对宿主免疫的成功至关重要。我们还将检测患有亚临床肠道地图感染的小牛肠道内的伽马-德尔塔T细胞，以及它们如何指导持续感染(潜伏期)的维持或向临床疾病的进展。这一结果将导致改进减少分枝杆菌感染和识别亚临床感染者的策略，以及加强对先天性免疫细胞在控制细菌感染中的作用的认识。

This research is designed to enhance our understanding of host innate immunity and resistance to mycobacterial infection. I am interested in how interactions between host innate immune cells and invading mycobacteria influence the outcome of infection. Mycobacterium avium subspecies paratuberculosis (Map) causes Johne's disease, an important and costly intestinal disease affecting beef and dairy cattle in Canada and around the world. Global efforts to control mycobacterial infections including Map have achieved limited success and this is largely because the fundamental mechanisms leading to success (elimination of infection) or failure (establishment of persistent infection) of host immunity are unknown. Gamma-delta T lymphocytes are a unique class of innate immune cells that have been recently implicated as orchestrators of host defense by directing adaptive immunity which is known to be essential for clearance of invading mycobacteria. We have observed recruitment of gamma-delta T cells to Map infection sites in calves, but a mechanistic understanding of their function in host immunity has not been elucidated. In these studies, we will investigate how these innate cells direct host immunity during initial Map infection: 1) how they are recruited to early infection sites and 2) how they affect function of other immune cells (macrophages, dendritic cells) which are vital for success of host immunity. We will also examine gamma-delta T cells within the intestine of calves with subclinical intestinal Map infection, and how they direct either maintenance of persistent infection (latency) or progression to clinical disease. The results will lead to improved strategies to reduce mycobacterial infections and identify subclinically-infected individuals as well as enhanced recognition of the role of innate immune cells in controlling bacterial infections.