A Novel Mechanism of Innate Immunity Against TB

描述(由申请人提供)：结核病(TB)作为全球 由于感染和抗药性的高流行率而引起的健康问题。更多 需要对结核病发病机制的详细知识来揭开治疗结核病的新方法 预防和治疗。早期的抗菌机制是 先天免疫反应系统对感染艾滋病的结局至关重要 结核分枝杆菌(Mtb)在这个应用中，我们调查了一部小说 结核分枝杆菌的主要宿主细胞--人巨噬细胞(MP)如何抑制 当它们发生凋亡时，结核分枝杆菌生长。我们的初步数据显示， 感染结核分枝杆菌的MP细胞的凋亡与其 表现出很强的抗分枝杆菌活性，而坏死则促进 胞外细菌生长。我们进一步表明，强毒结核分枝杆菌能够 避免宿主MP的凋亡，而减毒的Mtb菌株H37Ra强烈 诱导细胞凋亡。我们推测，MP-凋亡通过以下方式限制结核分枝杆菌的生长 在凋亡小体内隔离杆菌和2)包装结核分枝杆菌用于快速 并通过新招募的吞噬细胞有效地清除。摄取游离Mtb 也与吞噬小体成熟受阻和不受限制有关 细胞内生长。我们认为包装在凋亡小体中的结核分枝杆菌 被国会议员的防御系统更有效地消除。我们将研究 未感染MP出现结核分枝杆菌时可能的协同效应系统 包含在凋亡小体中。我们还发现Mtb诱导MP细胞凋亡。 和相关的抗分枝杆菌活性依赖于 肿瘤坏死因子a、胞浆磷脂酶A2等的作用 细胞内水平，但这些机制的特定角色和功能 是不理解的。我们将调查这些机制在 诱导细胞凋亡和抗分枝杆菌活性及其如何减弱和 毒力结核分枝杆菌在激活这些过程方面有所不同。因此，我们的目标是 1)确定无毒结核分枝杆菌如何诱导细胞凋亡和抗分枝杆菌 机制和毒力结核杆菌如何避免它，2)找出凋亡的MP是如何阻止的 结核分枝杆菌的生长和3)确定天然MP的抗分枝杆菌机制 在摄取凋亡感染的MP后。

DESCRIPTION (provided by the applicant): Tuberculosis (TB) persists as a global health concern due to high prevalence of infection and drug resistance. More detailed knowledge of TB pathogenesis is needed to unravel novel approaches for prevention and treatment. Early antimicrobial mechanisms which are part of the innate immune response system are crucial for the outcome of the infection with Mycobacterium tuberculosis (Mtb). In this application, we investigate a novel mechanism, how human macrophages (Mp), the primary host cell of Mtb, inhibit growth of Mtb when they undergo apoptosis. Our preliminary data show that apoptosis of the Mp infected with Mtb is associated with their capacity to exhibit strong anti-mycobacterial activity, whereas necrosis promotes extracellular bacterial growth. We further showed that virulent Mtb are able to avoid host Mp apoptosis, whereas the attenuated Mtb strain H37Ra strongly induces apoptosis. We postulate that Mp-apoptosis 1) restricts Mtb growth by sequestering the bacilli within apoptotic bodies and 2) packages Mtb for rapid and efficient elimination by freshly recruited phagocytes. Uptake of free Mtb is also associated with arrested phagosome maturation and unrestricted intracellular growth. We think that Mtb packaged in apoptotic bodies are eliminated more effectively by the defense systems of the Mp. We will examine possible cooperative effector systems when uninfected Mp are presented with Mtb contained in apoptotic bodies. We have also found that Mtb-induced Mp apoptosis and associated anti-mycobacterial activity are dependent on the concerted action of tumor necrosis factor a, cytosolic phospholipase A2, and on intra-cellular Calevels, but the specific role and function of these mechanisms is not understood. We will investigate the role of these mechanisms in induction of apoptosis and anti-mycobacterial activity and how attenuated and virulent Mtb differ in the activation of these processes. The goals, thus, are to 1) determine how avirulent Mtb induce apoptosis and antimycobacterial mechanisms and how virulent Mtb avoid it, 2) to find out how apoptotic Mp block growth of Mtb and 3) to define the anti-mycobacterial mechanisms of naive Mp after uptake of apoptotic infected Mp.