ANTIMYCOBACTERIAL MECHANISMS OF APOPTOSIS IN THE LUNG

肺细胞凋亡的抗真菌机制

• 批准号: 6627551
• 负责人: Hardy Kornfeld
• 金额: $ 40.82万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627551
• 关键词: Mycobacterium tuberculosis; alveolar macrophages; apoptosis; bactericidal immunity; bronchoscopy; clinical research; human subject

DESCRIPTION (Applicant's Abstract): Innate antimicrobial mechanisms of resident alveolar macrophages (AM) and control bacterial replication early in pulmonary tuberculosis, prior to the expression of adaptive immunity. The goal of this project is to study how AM suppress growth of Mycobacterium tuberculosis (Mtb). Our preliminary data indicate that growth of intracellular mycobacteria is efficiently restricted when AM undergo apoptosis, whereas necrosis promotes unrestricted extracellular bacterial replication. Apoptosis induced by several different pathways has been linked to this antimicrobial effect by other investigators as well, but a mechanism of this effect has not been proposed. We previously discovered that infection with Mtb directly activates TNFa death signaling in AM which we postulate limits bacterial growth by i) sequestering bacilli in apoptotic bodies and ii) marking infected cells for engulfment by phagocytes that recognize apoptotic epitopes. Phagocytosis of free Mtb is associated with arrested phagosome maturation and unrestricted intracellular growth of bacilli. We hypothesize that mycobacteria packaged by apoptosis are attacked by intracellular antimicrobial effector systems more effectively than occurs when free bacilli are internalized. It has recently been discovered that human dendritic cells efficiently present antigen derived from apoptotic cells by a process called "antigen cross-priming." Experiments in this project examine cooperative antimicrobial when naive AM are presented with Mtb by apoptotic AM, a process that we call "pathogen cross-priming." This system mimics events that occur in the lung in vivo where initial infection of AM by Mtb promotes recruitment of naive AM and other mononuclear phagocytes to the site of infection. The cellular requirements, apoptosis-specific epitopes, and intracellular effector mechanisms triggered by these interactions will be investigated. Together, these studies will characterize a novel host defense mechanism in tuberculosis that may represent a fundamental process relevant to a variety of intracellular lung pathogens.

描述（申请人的摘要）：居民先天抗菌机制 肺泡（AM）和对照细菌复制早期的肺泡巨噬细胞 结核病，在自适应免疫表达之前。目标的目标 项目是研究如何抑制结核分枝杆菌（MTB）的生长。 我们的初步数据表明，细胞内分枝杆菌的生长是 当AM发生凋亡时有效限制，而坏死促进 无限制的细胞外细菌复制。几个诱导的凋亡 不同的途径已与其他途径与这种抗菌作用联系在一起 研究人员也没有提出过这种作用的机制。我们 以前发现用MTB感染直接激活TNFA死亡 AM中的信号传导，我们假设通过i）隔离来限制细菌的生长 凋亡人士中的杆菌和ii）标记被感染的细胞以吞噬 识别凋亡表位的吞噬细胞。自由mtb的吞噬作用是 与被捕的吞噬体成熟和细胞内无限制有关 杆菌的生长。我们假设细胞凋亡包装的分枝杆菌是 比细胞内抗微生物效应器系统攻击比 自由细菌被内在化时发生。最近发现 人树突状细胞有效地呈现源自凋亡细胞的抗原 通过称为“抗原交叉染色”的过程。这个项目的实验 当天真的AM与MTB呈现MTB时，检查合作抗菌剂 凋亡AM，我们称之为“病原体交叉染色”的过程。这个系统 模仿体内肺部发生的事件，其中AM初始感染AM MTB促进幼稚AM和其他单核吞噬细胞的招募 感染部位。细胞需求，细胞凋亡特异性表位和 这些相互作用触发的细胞内效应器机制将是 调查。这些研究将共同​​描述一个新颖的宿主防御 结核病的机制可能代表与 各种细胞内肺病原体。