THE ROLE OF UBIQUILINS IN INNATE IMMUNITY TO TUBERCULOSIS

泛素在结核病先天免疫中的作用

• 批准号: 8636559
• 负责人: JENNIFER A PHILIPS
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636559
• 关键词: Accounting; Adaptor Signaling Protein; Affect; Antibodies; Antigen Presentation; Autophagocytosis; Autophagosome; Bacillus (bacterium); Bacteria; Bacterial Proteins; Binding; Cells; Collaborations; Cytoplasm; Cytosol; DNA; Dana-Farber Cancer Institute; Disease; Epidemic; Face; Family; Family member; Future; Genus Mycobacterium; Goals; Growth; HIV; Host Defense; Host resistance; Human; Immune; Individual; Infectious Agent; Laboratories; Light; Link; Listeria; Lysosomes; Maps; Membrane Proteins; Microtubule-Associated Proteins; Modeling; Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Natural Immunity; Open Reading Frames; Pathway interactions; Phagosomes; Play; Population; Predisposition; Proteins; Resistance; Role; Salmonella; Streptococcus pyogenes; Surface; System; Testing; Tuberculosis; Tuberculosis Vaccines; UBA Domain; Work; World Health Organization; Yeasts; antimicrobial; bacterial resistance; burden of illness; global health; improved; in vivo; insight; killings; macrophage; major urinary proteins; multicatalytic endopeptidase complex; mycobacterial; novel therapeutics; pathogen; public health relevance; research study; therapeutic development; trafficking; tuberculosis immunity; ubiquilin; vaccine development; yeast two hybrid system

DESCRIPTION (provided by applicant): Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). The World Health Organization estimates that in 2011 approximately 1.4 million people died from tuberculosis (TB), more people than from any other single infectious agent except for HIV. Mtb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. Although the worldwide disease burden is enormous, it remains poorly understood as to what accounts for successful host resistance and why it fails in 10% of infected individuals. Recent work has demonstrated the importance of autophagy in host resistance to bacterial pathogens. Autophagy is a general phenomenon by which host cells eradicate diverse bacteria, including human pathogens such as Listeria, Salmonella, Group A Streptococcus, and mycobacteria. A prevailing model of how autophagy contributes to host defense begins with bacteria damaging or escaping from phagosomes, followed by recognition of the bacteria by adaptor proteins such as p62 and Ndp52, which contain an ubiquitin associated (UBA) domain that binds ubiquitinated proteins and an LC3 binding motif. These adaptors are thought to link bacterial cargo to the autophagosome, although the determinants that are recognized on the bacteria are not known. Once captured in an autophagosome, bacterial replication is curtailed as the autophagosome fuses with lysosomes to form an autolysosome. Our work has identified 13 Mtb surface proteins (which we refer to as MUPs for Mycobacterial-Ubiquilin (Ubqln)- interacting Proteins) that interact with a family of related host proteins, Ubiquilin 1, Ubiquilin 2, and Ubiquilin 4, that ar implicated in autophagy and proteasomal degradation. We hypothesize that the interaction between Ubqln1 and MUPs results in targeting of intact Mtb bacilli and/or MUPs for degradation. The goal of this proposal is to determine whether Ublqn1 links Mtb and/or MUPs to the autophagy or proteasomal pathway, and thereby regulates intracellular Mtb survival, degradation of MUPs, and/or antigen presentation. These experiments have important implications for Mtb vaccine development and will provide insight into the anti- microbial capacity of macrophages. Ultimately, we might be able to improve the mycobacterial killing capacity of the infected macrophage. This would enable novel therapeutic development that could significantly shorten therapy, and in turn, change the face of the global epidemic. In addition, given the conservation of MUPs, this work may offer insight into innate resistance to an array of bacterial pathogens.

描述（由申请人提供）：世界上大约三分之一的人口感染结核分枝杆菌（Mtb）。世界卫生组织估计，2011年约有140万人死于结核病，比除艾滋病毒以外的任何其他单一传染病都多。结核病能够通过破坏宿主的先天性和适应性防御来建立这种巨大的全球性疾病负担。尽管世界范围内的疾病负担是巨大的，但对于成功的宿主抗性的原因以及为什么它在10%的感染个体中失败仍然知之甚少。最近的工作已经证明了自噬在宿主抵抗细菌病原体中的重要性。自噬是宿主细胞消灭多种细菌的普遍现象，包括人类病原体如李斯特菌、沙门氏菌、A组链球菌和分枝杆菌。自噬如何有助于宿主防御的流行模型开始于细菌破坏或逃离吞噬体，随后通过衔接蛋白如p62和Ndp 52识别细菌，其含有结合泛素化蛋白的泛素相关（乌巴）结构域和LC 3结合基序。这些衔接子被认为将细菌货物与自噬体连接起来，尽管细菌上识别的决定簇尚不清楚。一旦被自噬体捕获，细菌的复制就会随着自噬体与溶酶体融合形成自溶酶体而减少。我们的工作已经鉴定了13种Mtb表面蛋白（我们称之为分枝杆菌-泛素（Ubqln）相互作用蛋白的MUP），它们与相关宿主蛋白家族（Ubiquilin 1、Ubiquilin 2和Ubiquilin 4）相互作用，这些蛋白与自噬和蛋白酶体降解有关。我们假设Ubqln 1和MUP之间的相互作用导致靶向完整的Mtb杆菌和/或MUP进行降解。该提议的目标是确定Ublqn 1是否将Mtb和/或MUP与自噬或蛋白酶体途径联系起来，从而调节细胞内Mtb存活、MUP降解和/或抗原呈递。这些实验对Mtb疫苗开发具有重要意义，并将提供对巨噬细胞抗微生物能力的深入了解。最终，我们可能能够提高受感染巨噬细胞的分枝杆菌杀伤能力。这将使新的治疗方法的发展，可以大大缩短治疗，并反过来改变全球流行病的面貌。此外，鉴于MUP的保守性，这项工作可能会提供对一系列细菌病原体的先天抗性的见解。