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（由适用提供）：持续的艾滋病毒/艾滋病流行和多药耐药性分枝杆菌结核病（MTB）的传播使世界各地人群中的结核病流行永久存在。尽管BCG普遍用作疫苗，但它在预防肺结核方面无效。为了打击这种正在进行的全球搜查，重中之重是结核病的疫苗开发。凋亡是一种先天的Mφ防御机制，可限制细菌复制并限制MTB的分散体。凋亡还连接了先天和克隆免疫。 DC呈现细菌抗原在凋亡蔬菜中包装到T细胞中，从而在体内提供更好的T细胞启动和保护。如何调节凋亡以及 限制MTB复制以及是否可以操纵它以增强疫苗接种是该提案的重点。创新：类花生酸在对分枝杆菌免疫中的作用在鱼类，小鼠和人类中保存下来，强调了它们的基本重要性。我们发表的有关体外感染的人Mφ和体内感染小鼠的工作，将MTB感染的Mφ作为针对结核病的至关重要的宿主防御机制。直到最近才对MTB感染Mφ的死亡途径的复杂性得到理解。有毒的MTB影响Lipoxin A4（LXA4），抑制前列腺素E2（PGE2）合成，阻断凋亡并促进坏死Mφ死亡。相反，PGE2可预防坏死并增加凋亡。为什么不了解凋亡作为宿主防御机制。在这里，我们提出了一个新的假设，即导致控制的不是凋亡本身，而是对MTB感染的凋亡Mφ的吞噬作用，这是关键事件。我们预测：（1）Mφ的吞噬作用将包含感染； （2）DC的吞噬作用将导致幼稚的T细胞启动。除了类花生酸的途径外，IL-1ß与I型IFN（IFNß）之间的平衡也作为影响先天和克隆免疫力的第二轴。我们提出了一个新模型，其中MTB诱导的LXA4和IFNß都相互作用以抑制先天的免疫力，而PGE2，IL-1ß和TNF促进了抗菌免疫。目的：在AIM 1中，我们将确定类花生酸如何调节感染巨噬细胞的激活并诱导细胞内细菌复制的控制。特别是，我们将确定类固醇如何影响IL-1ß和I型IFN（IFNß）之间的平衡，这是影响先天和克隆免疫力的第二轴。在第二个目的中，我们将检验以下假设：杀死MTB的不是凋亡本身 - 而是吞噬吞噬作用限制了细胞内MTB生长的吞噬作用。凋亡细胞的吞噬作用称为肿瘤，是主要组成型Mφ功能。但是，对其在感染中的作用知之甚少。最后，在第三个目标中，我们将确定eicosanoids凋亡与克隆免疫抑制之间的关系。我们假设可以在药理上操纵类类生物合成和细胞信号通路以增强感染Mφ的凋亡。通过促进凋亡死亡，我们希望提高减毒细菌疫苗的安全性和有效性。我们认为，对促凋亡疫苗如何诱导更好的免疫力的机械理解将导致针对结核病和其他使用分枝杆菌载体的疾病的更好的免疫接种策略。摘要：更好地理解凋亡和吞噬作用如何影响先天免疫学，以控制细菌复制和刺激T细胞免疫学的MTB，将改善我们对TB发病机理的理解，并将导致对新疗法的研究。