Apoptosis and efferocytosis: regulators of immunity to tuberculosis

描述（由申请人提供）：持续的艾滋病毒/艾滋病流行和多药耐药结核分枝杆菌（Mtb）的传播使结核病在世界各地的人群中持续流行。虽然卡介苗是一种普遍使用的疫苗，但它在预防肺结核方面并不有效。为防治这一持续不断的世界祸害，开发结核病疫苗是一项优先事项。细胞凋亡是一种先天的Mφ防御机制，它限制了结核菌的复制和扩散。细胞凋亡也与先天免疫和克隆免疫有关。DC将包装在凋亡囊泡中的细菌抗原呈递到T细胞，在体内导致更好的T细胞启动和保护。细胞凋亡是如何调控的

DESCRIPTION (provided by applicant): The continuing HIV/AIDS epidemic and the spread of multi-drug resistant Mycobacterium tuberculosis (Mtb) has perpetuated an epidemic of tuberculosis in human populations around the world. While BCG is used universally as a vaccine, it is not effective in preventing pulmonary tuberculosis. To combat this ongoing worldwide scourge, vaccine development for tuberculosis is a priority. Apoptosis is an innate Mφ defense mechanism that limits bacterial replication and restricts dispersal of Mtb. Apoptosis also links innate and clonal immunity. DC present bacterial antigens packaged in apoptotic vesicles to T cells, leading to better T cell priming and protection in vivo. How apoptosis is regulated and restricts Mtb replication and whether it can be manipulated to enhance vaccination is the focus of this proposal. Innovation: The role of eicosanoids in immunity to mycobacteria is conserved in fish, mice and humans, highlighting their fundamental importance. Our published work on in vitro infected human Mφ and on in vivo infected mice establish apoptosis of Mtb infected Mφ as a critically important host defense mechanism against tuberculosis. The complexity of death pathways in Mtb infected Mφ has only recently been appreciated. Virulent Mtb induces lipoxin A4 (LXA4), inhibits prostaglandin E2 (PGE2) synthesis, blocks apoptosis, and promotes necrotic Mφ death. In contrast, PGE2 protects against necrosis and increases apoptosis. Why apoptosis acts as a host defense mechanism is not understood. Here we put forward a new hypothesis that it is not apoptosis per se that leads to control, but instead phagocytosis of Mtb infected apoptotic Mφ that is the crucial event. We predict: (1) phagocytosis by Mφ will contain the infection; and (2) phagocytosis by DC will lead to priming of naïve T cells. In addition to the eicosanoid pathways, the balance between IL-1ß and type I IFN (IFNß) is emerging as a second axis that affects innate and clonal immunity. We propose a new model in which LXA4 and IFNß, both induced by Mtb, interact to inhibit innate immunity, while PGE2, IL-1ß and TNF promote antibacterial immunity. Aims: In Aim 1, we will determine how eicosanoids regulate activation of infected macrophages and induce control of intracellular bacterial replication. In particular, we will determine how eicosanoids affect the balance between IL-1ß and type I IFN (IFNß), which is emerging as a second axis that affects innate and clonal immunity. In the second aim, we will test the hypothesis that it is not apoptosis per se that kills Mtb - rather it is the phagocytosis f infected apoptotic Mφ that restricts intracellular Mtb growth. Phagocytosis of apoptotic cells, termed efferocytosis, is a major constitutive Mφ function; however, little is known about its role during infection. Finally, in the third aim, we will determine the relationship between eicosanoids apoptosis and clonal immunity. We hypothesize that the eicosanoid biosynthetic and cell signaling pathways can be pharmacologically manipulated to enhance apoptosis of infected Mφ. By promoting apoptotic death, we hope to increase the safety and the efficacy of attenuated bacterial vaccines. We believe that a mechanistic understanding of how pro-apoptotic vaccines induce better immunity will lead to the development of better immunization strategies against tuberculosis and other diseases that are using mycobacterial vectors. Summary: A better understanding of how apoptosis and efferocytosis affect innate immunity to Mtb culminating in control of the bacterial replication and stimulation of T cell immunity will improve our understanding of TB pathogenesis and will lead to research into novel therapies.