A Novel Mechanism of Innate Immunity Against TB

结核病（TB）由于感染和耐药性的高流行率而作为全球健康问题持续存在。 需要更详细地了解结核病的发病机制，以揭示预防和治疗的新方法。 作为先天免疫应答系统的一部分，早期抗微生物机制对于结核分枝杆菌（Mtb）感染的结果至关重要。 在这个应用程序中，我们调查了一种新的机制，如何人巨噬细胞（Mphi），结核分枝杆菌的主要宿主细胞，抑制结核分枝杆菌的生长时，他们进行凋亡。 我们的初步数据表明，Mphi感染Mtb的细胞凋亡与它们表现出强抗分枝杆菌活性的能力有关，而坏死促进细胞外细菌生长。 我们进一步表明，毒性Mtb能够避免宿主Mphi细胞凋亡，而减毒Mtb菌株H37 Ra强烈诱导细胞凋亡。 我们假设Mphi-凋亡1）通过将杆菌隔离在凋亡小体内来限制Mtb生长，以及2）包装Mtb以通过新鲜募集的吞噬细胞快速有效地消除。 游离Mtb的摄取也与吞噬体成熟停滞和细胞内生长不受限制有关。 我们认为Mphi的防御系统更有效地消除了包装在凋亡小体中的Mtb。 我们将研究可能的合作效应系统时，未感染的Mphi与Mtb的凋亡小体。 我们还发现结核分枝杆菌诱导的Mphi细胞凋亡和相关的抗分枝杆菌活性依赖于肿瘤坏死因子α、胞浆磷脂酶A2和细胞内Ca++水平的协同作用，但这些机制的具体作用和功能尚不清楚。 我们将研究这些机制在诱导细胞凋亡和抗分枝杆菌活性中的作用，以及减毒和毒性结核分枝杆菌在这些过程的激活中的差异。 因此，目标是1）确定毒性Mtb如何诱导细胞凋亡和抗分枝杆菌机制以及毒性Mtb如何避免细胞凋亡和抗分枝杆菌机制，2）找出细胞凋亡的Mphi如何阻断Mtb的生长，以及3）定义在摄取细胞凋亡的感染的Mphi之后初始Mphi的抗分枝杆菌机制。

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 (Mphi), the primary host cell of Mtb, inhibit growth of Mtb when they undergo apoptosis. Our preliminary data show that apoptosis of the Mphi 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 Mphi apoptosis, whereas the attenuated Mtb strain H37Ra strongly induces apoptosis. We postulate that Mphi- 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 Mphi. We will examine possible cooperative effector systems when uninfected Mphi are presented with Mtb contained in apoptotic bodies. We have also found that Mtb-induced Mphi apoptosis and associated anti-mycobacterial activity are dependent on the concerted action of tumor necrosis factor alpha, cytosolic phospholipase A2, and on intra-cellular Ca++ levels, 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 a virulent Mtb induce apoptosis and anti- mycobacterial mechanisms and how virulent Mtb avoid it, 2) to find out how apoptotic Mphi block growth of Mtb and 3) to define the anti-mycobacterial mechanisms of naive Mphi after uptake of apoptotic infected Mphi.