A Novel Mechanism of Innate Immunity Against TB

由于高感染率和高耐药性，结核病仍然是全球关注的健康问题。需要对结核病发病机制有更详细的了解，以揭示新的预防和治疗方法。早期的抗菌机制是先天免疫反应系统的一部分，对结核分枝杆菌(Mtb)感染的结局至关重要。在这一应用中，我们研究了一种新的机制，人巨噬细胞(Mphi)，结核分枝杆菌的主要宿主细胞，在结核分枝杆菌发生凋亡时如何抑制它们的生长。我们的初步数据显示，感染结核分枝杆菌的Mphi细胞的凋亡与其显示出强大的抗分枝杆菌活性有关，而坏死则促进细胞外细菌的生长。我们进一步表明，强毒Mtb能够避免宿主Mphi的凋亡，而减毒的Mtb菌株H37Ra强烈诱导细胞凋亡。我们推测，Mphi-凋亡率1)通过隔离凋亡小体内的细菌来限制结核分枝杆菌的生长，2)包装结核分枝杆菌使其快速有效地被新招募的吞噬细胞消除。摄取游离Mtb还与吞噬小体成熟受阻和细胞内不受限制的生长有关。我们认为，Mphi的防御系统可以更有效地清除包装在凋亡小体中的结核分枝杆菌。我们将研究当未感染的Mphi出现凋亡小体中含有Mtb时，可能的合作效应系统。我们还发现，Mtb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和细胞内钙离子水平的协同作用，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，以及减毒和毒力结核杆菌在激活这些过程中的不同之处。因此，我们的目标是1)确定毒力Mtb如何诱导细胞凋亡和抗分枝杆菌的机制，以及毒力Mtb如何避免它，2)找出凋亡的Mphi如何阻止Mtb的生长，以及3)确定Naive Mphi在摄取凋亡感染的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.