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: 9062959
• 负责人: JENNIFER A PHILIPS
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 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/9062959
• 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; Health; 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; 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(申请人提供)：大约三分之一的世界人口感染结核分枝杆菌(结核杆菌)。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致死的人数都多。结核分枝杆菌能够通过颠覆宿主的固有和适应性防御来建立这种巨大的全球疾病负担。尽管全世界的疾病负担是巨大的，但人们仍然不太清楚是什么原因导致了宿主抗药性的成功，以及为什么在10%的感染者中抗药性失败了。最近的工作证明了自噬在宿主抵抗细菌病原体方面的重要性。自噬是宿主细胞清除各种细菌的一种普遍现象，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。自噬如何有助于宿主防御的一个流行模型始于细菌破坏或逃离吞噬小体，然后是接合蛋白识别细菌，如p62和Ndp52，它们包含一个结合泛素化蛋白的泛素相关(UBA)结构域和一个LC3结合基序。这些适配器被认为将细菌货物与自噬小体联系起来，尽管细菌上识别的决定因素尚不清楚。一旦被自噬小体捕获，细菌的复制就会受到抑制，因为自噬小体与溶酶体融合形成自溶酶体。我们的工作已经确定了13个Mtb表面蛋白(我们称为分枝杆菌-泛素蛋白(Ubqln)相互作用蛋白)，它们与一系列相关的宿主蛋白Ubiqulin 1、Ubiqulin 2和Ubiqulin 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Ubqln1和MUPs之间的相互作用导致靶向完整的Mtb杆菌和/或MUPs进行降解。这项建议的目的是确定Ublqn1是否将Mtb和/或MUPs与自噬或蛋白酶体途径联系起来，从而调节细胞内Mtb的存活、MUP的降解和/或抗原递呈。这些实验对结核分枝杆菌疫苗的开发具有重要意义，并将提供对巨噬细胞抗微生物能力的洞察。最终，我们可能能够提高受感染巨噬细胞的分枝杆菌杀伤力。这将使新的治疗方法能够显著缩短治疗时间，进而改变全球流行病的面貌。此外，考虑到MUPs的保守性，这项工作可能提供对一系列细菌病原体的先天抵抗力的洞察。