A Novel Mechanism of Innate Immunity Against TB

由于结核病的高感染率和耐药性，结核病一直是全球关注的健康问题。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结核分枝杆菌感染的结果至关重要。在这个应用程序中，我们研究了一种新的机制，即人巨噬细胞（Mphi），结核分枝杆菌的原代宿主细胞，如何在细胞凋亡时抑制结核分枝杆菌的生长。我们的初步数据表明，感染结核分枝杆菌的Mphi的凋亡与它们表现出强抗分枝杆菌活性的能力有关，而坏死则促进细胞外细菌的生长。我们进一步发现，强毒Mtb能够避免宿主Mphi细胞凋亡，而弱毒Mtb菌株H37Ra则强烈诱导宿主Mphi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结核分枝杆菌的生长，2)将结核分枝杆菌包裹起来，以便新招募的吞噬细胞快速有效地消除结核分枝杆菌。游离结核分枝杆菌的摄取也与吞噬体成熟受阻和细胞内生长不受限制有关。我们认为包装在凋亡小体中的Mtb被Mphi的防御系统更有效地清除。当未感染的Mphi与凋亡小体中含有的Mtb一起呈现时，我们将研究可能的协同效应系统。我们还发现mmb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、胞质磷脂酶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，以及减毒结核分枝杆菌和强毒结核分枝杆菌在这些过程的激活中有何不同。因此，我们的目标是：1)确定毒性Mtb如何诱导细胞凋亡和抗分枝杆菌的机制，以及毒性Mtb如何避免这种机制；2)发现凋亡的Mphi如何阻断Mtb的生长；3)确定未处理的Mphi在摄入凋亡感染的Mphi后的抗分枝杆菌机制。

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.