Manipulation of Macrophage Responses by M. tuberculosis

结核病(TB)是一种持续的肺部感染，已困扰人类数百年， 被列为当今世界卫生最严重的威胁之一。200-300万人的死亡归因于 每年都会出现结核病，以及对所有可用化疗药物产生抗药性的菌株的出现，迫切需要开发新的疗法来治疗结核病。 -是的， -3- 0.o 此外，耐药结核病作为生物恐怖主义制剂的威胁已导致其被列为NIAID生物防御研究的C类优先病原体。结核杆菌如何与宿主细胞相互作用以便在感染期间生长还不是很清楚。这项拟议研究的主要目标是了解这种病原体触发和操纵其主要宿主细胞-巨噬细胞的宿主反应的机制。从我们的转录图谱工作中，我们发现结核分枝杆菌，一种空泡病原体，引起起源于受感染巨噬细胞胞浆的反应。然而，这种反应的激发完全依赖于细菌ESX-1的分泌系统，为调节宿主反应的微生物参与者提供了一个意想不到的窗口。我们假设结核分枝杆菌胞液监视通路的激活对宿主控制很重要，该通路激活的基因起到保护宿主免受感染的作用。这里提出的研究将测试这一模型，并提供在结核分枝杆菌感染早期阶段至关重要的宿主-病原体相互作用的分子细节。具体地说，我们将确定巨噬细胞感知结核分枝杆菌感染启动胞液监视途径的机制，还将确定巨噬细胞感知的细菌分子(S)，并确定它们如何进入胞浆。最终，通过在分子水平上了解结核病的发病机制，我们希望有助于发现新的治疗方法来对抗和根除这种持续感染。由于巨噬细胞的胞浆识别在许多细菌感染中是保守的，了解其功能可能会导致开发新的治疗方法和诊断范围广泛的传染病。同样，阐明针对结核分枝杆菌的特异性反应可能有助于开发新的结核病治疗和诊断方法。 --�a (吉普 提‘ 5.0.0-0 3.0 第七章 问：“ .N。 &lt；.&lt； N‘.&lt； 共同-- (-j .N-。 N�33� -+。 (1) O(D) (ND) E 目标 _U- �)S ：. A)&gt；

Tuberculosis (TB) is a persistent lung infection that has plagued mankind for centuries and ranks as one of the most serious threats to world health today. The 2-3 million deaths attributed yearly to the disease, as well as the emergence of strains resistant to all of the available chemotherapeutic agents, urgently call for the development of new therapies to treat TB. -y, -3- 0.o Furthermore, the threat of drug-resistant TB as a bioterrorism agent has led to it's listing as a NIAID Category C Priority Pathogen for biodefense research. How the TB bacillus interacts with host cells in order to grow during infection is not well understood. The primary objective of the proposed research is to understand the mechanisms by which this pathogen triggers and manipulates host responses of its primary host cell, the macrophage. From our transcriptional profiling work, we found that M. tuberculosis, a vacuolar pathogen, elicits an response that originates in the cytosol of infected macrophages. lmportanfly, elicitation of this response depends completely on the bacterial ESX-1 secretion system, providing an unexpected window into microbial players that modulate the host response. We hypothesize that activation of the cytosolic surveillance pathway by M. tuberculosis is important for host control and that genes activated by the pathway work to protect the host from infection. The studies proposed here will test this model and provide molecular details of host-pathogen interactions critical during the early stages of M. tuberculosis infection. Specifically, we will determine the mechanism by which macrophages sense M. tuberculosis infection to initiate the cytosolic surveillance pathway and also identify the bacterial molecule(s) sensed by macrophages and determine how they gain access to the cytosol. Ultimately, by understanding tuberculosis pathogenesis at the molecular level, we hope to aid in the discovery of new therapies to combat and eradicate this persistent infection. Because cytosolic recognition by macrophages is conserved in many bacterial infections, understanding its function may lead to the development of new treatments and diagnostics for a broad range of infectious diseases. Likewise, elucidating the responses specific to M. tuberculosis may help in the development of new TB treatments and diagnostics. -�a (gyp ti' 5.0.0-0 3.0 vii Q." .n. <.< n'.< Co- (-j .N-. n�33� -+. (1) O(D (ND E aim _U- �)s :.. a)>