Manipulation of Macrophage Responses by M. tuberculosis

结核病（TB）是一种持续性肺部感染，已困扰人类数百年， 是当今世界卫生面临的最严重威胁之一。200万至300万人死亡 结核病每年的发病率，以及对所有可用化疗药物产生耐药性的菌株的出现，迫切要求开发新的治疗结核病的疗法。 -y， -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在感染期间生长尚不清楚。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。从我们的转录谱工作，我们发现，M。肺结核是一种空泡病原体，它激发了一种起源于受感染巨噬细胞胞质溶胶的反应。重要的是，该应答的引发完全取决于细菌ESX-1分泌系统，从而为调节宿主应答的微生物参与者提供了意想不到的窗口。我们推测M.结核病对于宿主控制是重要的，并且由该途径激活的基因起保护宿主免受感染的作用。本文提出的研究将检验这一模型，并提供在M.肺结核感染。具体地说，我们将确定巨噬细胞感知M的机制。本发明的目的在于检测结核感染以启动胞质监视途径，并且还鉴定由巨噬细胞感知的细菌分子并确定它们如何进入胞质。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性感染。由于巨噬细胞的胞质识别在许多细菌感染中是保守的，因此了解其功能可能会导致开发用于广泛感染性疾病的新治疗和诊断方法。同样，阐明了M.结核病的研究可能有助于开发新的结核病治疗和诊断方法。 �系我�� （gyp 醍 5.0.0-0 3.0 VII Q. " . n. <. < 不。< 共 （-j .N-。 �P于我�� -+. （一） O（D （ND E 目的 - U- �）s :.. （a）>

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)>