THE ROLE OF UBIQUILINS IN INNATE IMMUNITY TO TUBERCULOSIS

泛素在结核病先天免疫中的作用

基本信息

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
项目类别：
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

项目摘要

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）：大约三分之一的世界人口感染了结核分枝杆菌（MTB）。世界卫生组织估计，在2011年，大约有140万人死于结核病（TB），除了艾滋病毒以外，其他任何单一的传染剂人数都要多。 MTB能够通过颠覆宿主的先天和适应性防御能力来建立这一巨大的疾病负担。尽管全球疾病负担巨大，但对于成功占据宿主抵抗的原因以及为什么10％的受感染者失败的原因仍然很糟糕。最近的工作表明，自噬在宿主对细菌病原体的抗性中的重要性。自噬是一种普遍的现象，宿主细胞消除了各种细菌，包括李斯特菌，沙门氏菌，A组链球菌和分枝杆菌等人类病原体。一种流行的模型，讲述了自噬如何对宿主防御的贡献始于细菌损害或逃脱吞噬体，然后通过适配蛋白（例如p62和NDP52）识别细菌，这些蛋白质（含有泛素相关的（UBA）域）结合了构成泛蛋白蛋白和泛素蛋白质和LC3结合的依赖性。尽管尚不清楚，这些适配器被认为可以将细菌货物与自噬体联系起来，尽管在细菌上识别的决定因素尚不清楚。一旦被捕获在自噬体中，细菌复制就会减少与溶酶体的自噬体融合，形成自身溶血体。我们的工作已经确定了13个MTB表面蛋白（我们指的是分枝杆菌 - 纤维蛋白（UBQLN） - 相互作用蛋白的MUP），它们与相关宿主蛋白的家族相互作用，Ubiquilin 1，ubiquilin 2和Ubiquilin 4和Ubiquilin 4，尤比基蛋白4，尤其是自operapopyapy和Protophagagy和Protophapy Degrademation and Protophagy and protapy and protapy and protapy and protapy and protaby and protapy and protaby and protagy and。我们假设UBQLN1与MUP之间的相互作用导致靶向完整的MTB杆菌和/或MUP降解。该建议的目的是确定UBLQN1是否将MTB和/或MUP连接到自噬或蛋白酶体途径，从而调节细胞内MTB存活，MUP的降解和/或抗原表现。这些实验对MTB疫苗的发展具有重要意义，并将洞悉巨噬细胞的抗微生物能力。最终，我们可能能够提高感染巨噬细胞的分枝杆菌杀戮能力。这将使新的治疗性发育能够显着缩短治疗，进而改变全球流行病的面貌。此外，鉴于MUP的保护，这项工作可能会洞悉对一系列细菌病原体的先天抗性。