Apoptosis and efferocytosis: regulators of immunity to tuberculosis

细胞凋亡和胞吞作用：结核病免疫的调节因子

• 批准号: 8791297
• 负责人: SAMUEL M BEHAR
• 金额: $ 49.62万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791297
• 关键词: AIDS/HIV problem; Adoptive Transfer; Affect; Annexins; Anti-Bacterial Agents; Apoptosis; Apoptotic; Attenuated; Bacterial Antigens; Bacterial Vaccines; Biological Assay; Caspase; Cell Death; Cell surface; Cells; Cessation of life; Cytokine Signaling; Data; Defense Mechanisms; Development; Dinoprostone; Disease; Drug resistance in tuberculosis; Eating; Eicosanoids; Epidemic; Equilibrium; Event; Fishes; Genus Mycobacterium; Growth; Host Defense Mechanism; Host resistance; Human; Immune system; Immunity; Immunization; In Vitro; Infection; Infection Control; Interferons; Lead; Link; Lipoxins; Lysosomes; Mediator of activation protein; Modality; Modeling; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Natural Immunity; Necrosis; Nucleosomes; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Phagocytosis; Phosphatidylserines; Population; Prevention; Production; Publishing; Pulmonary Tuberculosis; Regulation; Reporting; Research; Research Proposals; Role; Safety; Scourge; Signal Pathway; Signal Transduction; T-Lymphocyte; TNF gene; Testing; Tuberculosis; Vaccination; Vaccines; Vesicle; Virulent; Work; base; combat; cytokine; global health; improved; in vivo; innovation; killings; lipoxin A4; macrophage; mycobacterial; novel; prevent; response; tuberculosis immunity; vaccine development; vector

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.

描述（由申请人提供）：持续的艾滋病毒/艾滋病流行和多重耐药结核分枝杆菌（Mtb）的传播使结核病在世界各地的人群中长期流行。虽然卡介苗被普遍用作疫苗，但它不能有效预防肺结核。为了对抗这一持续存在的世界性祸害，开发结核病疫苗是当务之急。细胞凋亡是一种先天的 Mφ 防御机制，可限制细菌复制并限制 Mtb 的扩散。细胞凋亡还与先天免疫和克隆免疫联系在一起。 DC 将包装在凋亡囊泡中的细菌抗原呈递给 T 细胞，从而在体内更好地启动和保护 T 细胞。细胞凋亡是如何调控的 限制结核分枝杆菌的复制以及是否可以操纵它来加强疫苗接种是该提案的重点。创新：类二十烷酸在分枝杆菌免疫中的作用在鱼、小鼠和人类中是保守的，这凸显了它们的根本重要性。我们发表的关于体外感染的人类 Mφ 和体内感染的小鼠的研究表明，Mtb 感染的 Mφ 的细胞凋亡是一种至关重要的宿主针对结核病的防御机制。 Mtb 感染 Mφ 死亡途径的复杂性直到最近才被认识到。强毒 Mtb 会诱导脂氧素 A4 (LXA4)、抑制前列腺素 E2 (PGE2) 合成、阻断细胞凋亡并促进坏死性 Mφ 死亡。相反，PGE2 可以防止坏死并增加细胞凋亡。为什么细胞凋亡充当宿主防御机制尚不清楚。在这里，我们提出了一个新的假设，即导致控制的不是细胞凋亡本身，而是Mtb感染的细胞凋亡Mφ的吞噬作用才是关键事件。我们预测：（1）Mφ的吞噬作用将抑制感染； (2) DC 的吞噬作用将导致初始 T 细胞的启动。除了类二十烷酸途径外，IL-1ß 和 I 型干扰素 (IFNß) 之间的平衡正在成为影响先天和克隆免疫的第二轴。我们提出了一种新模型，其中 LXA4 和 IFNß（均由 Mtb 诱导）相互作用，抑制先天免疫，而 PGE2、IL-1ß 和 TNF 则促进抗菌免疫。目标：在目标 1 中，我们将确定类二十烷酸如何调节受感染巨噬细胞的激活并诱导对细胞内细菌复制的控制。特别是，我们将确定类二十烷酸如何影响 IL-1ß 和 I 型干扰素 (IFNß) 之间的平衡，后者正在成为影响先天和克隆免疫的第二轴。在第二个目标中，我们将检验这样的假设：杀死 Mtb 的并不是细胞凋亡本身，而是受感染的细胞凋亡 Mφ 的吞噬作用限制了细胞内 Mtb 的生长。凋亡细胞的吞噬作用（称为胞吞作用）是 Mφ 的主要组成功能；然而，人们对其在感染过程中的作用知之甚少。最后，在第三个目标中，我们将确定类二十烷酸凋亡与克隆免疫之间的关系。我们假设类二十烷酸生物合成和细胞信号传导途径可以通过药理学操作来增强受感染 Mφ 的凋亡。通过促进细胞凋亡，我们希望提高减毒细菌疫苗的安全性和有效性。我们相信，对促凋亡疫苗如何诱导更好的免疫力的机制理解将有助于开发更好的免疫策略，以对抗结核病和其他使用分枝杆菌载体的疾病。摘要：更好地了解细胞凋亡和胞吞作用如何影响 Mtb 的先天免疫，最终控制细菌复制和刺激 T 细胞免疫，将提高我们对 TB 发病机制的理解，并将导致新疗法的研究。