Modulation of Host Cell Environment by Mycobacterial PE/PPE Proteins

分枝杆菌 PE/PPE 蛋白对宿主细胞环境的调节

基本信息

批准号：
10064574
负责人：
Sunhee Lee
金额：
$ 55.33万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064574
关键词：
Affect Antigen Presentation Attenuated Autophagocytosis Autophagosome BCG Vaccine Cell physiology Cells Complex Development Disease Encapsulated Ensure Environment Family Family member Frequencies Genes Genus Mycobacterium Goals Growth HIV Host Defense Immune Immune Evasion Immune response Immune system Immunity In Vitro Infection prevention Knowledge Lead Libraries Lysosomes MHC Class II Genes Mediating Microbe Modeling Molecular Multi-Drug Resistance Mus Mycobacterium Infections Mycobacterium bovis Mycobacterium tuberculosis Natural Immunity Nutrient Outcome Pathogenesis Pathogenicity Pathway interactions Phagocytes Phagolysosome Phagosomes Pharmacotherapy Phenotype Play Prevalence Prevention Progressive Disease Protein Family Proteins Research Role T cell response Testing Therapeutic Tuberculosis Tuberculosis Vaccines Vaccination Vaccine Design Vacuole Vesicle Virulence Virulence Factors Yeasts adaptive immunity co-infection extensive drug resistance gene complementation global health host-microbe interactions improved in vivo inhibition of autophagy inhibitor/antagonist innate immune pathways loss of function macrophage member mutant mycobacterial novel therapeutic intervention novel vaccines pathogen pathogenic bacteria pathogenic virus prevent public health relevance screening success trafficking vaccine access vaccine candidate vaccine development yeast two hybrid system

项目摘要

Abstract Autophagy, a key host defense pathway, has an essential role in both innate and adaptive immunity. However, many microbes have evolved mechanisms to evade, subvert, or exploit autophagy. Bacterial and viral pathogens can block autophagosome fusion with lysosomes to evade degradation, or utilize nutrients in such vesicles. It has been demonstrated that stimulation of autophagic pathways in macrophages causes mycobacterial phagosomes to mature into phagolysosomes, which can then overcome the trafficking block imposed by Mycobacterium tuberculosis. Thus, induction of autophagy can suppress intracellular survival of mycobacteria. We hypothesize that mycobacterial virulence factors mediate autophagy evasion in order to ensure survival within the infected macrophages. The identification and characterization of such virulence factors will allow us to understand the mechanisms by which autophagy affects the outcome of host-microbe interactions and immune responses. Through loss-of-function screening of mycobacteria using transposon mutant screening, we were able to identify thirteen chromosomal regions responsible for manipulating mycobacterial infection-induced autophagy. Remarkably, six of these regions contain genes belonging to the PE/PPE protein family that are especially abundant in pathogenic mycobacteria and have been shown to play diverse roles in mycobacterial pathogenesis and in modulating critical innate immune pathways. However, no PE/PPE proteins are known to be associated with autophagy pathways. Thus, the goals of this project are to investigate the roles and mechanisms of a subset of PE/PPE proteins and to determine the consequences of autophagic degradation of mycobacteria on innate and adaptive immunity. Increased knowledge of M. tuberculosis infection-induced autophagy presents an opportunity to uncover new and promising therapeutics against tuberculosis to prevent mycobacterial infection and survival within the host. Additionally, the pro- autophagic mutants generated in this study may have significant application in the development of effective, safe and persistent TB vaccines.

抽象的自噬是一种主要的宿主防御途径，在先天和适应性免疫中都起着至关重要的作用。然而，许多微生物具有进化的机制来逃避，颠覆或利用自噬。细菌和病毒病原体可以阻止自噬体融合与溶酶体以逃避降解，或在这种情况下利用营养囊泡。已经证明巨噬细胞中自噬途径的刺激分枝杆菌吞噬体成熟成吞噬体，然后可以克服贩运块由结核分枝杆菌施加。因此，自噬的诱导可以抑制细胞内存活分枝杆菌。我们假设分枝杆菌毒力因子介导自噬逃避，以便确保感染巨噬细胞内的生存。这种毒力的识别和表征因素将使我们能够理解自噬影响宿主 - 微叶结果的机制相互作用和免疫反应。通过使用转座子对分枝杆菌的功能丧失筛查突变筛选，我们能够识别负责操纵的13个染色体区域分枝杆菌感染引起的自噬。值得注意的是，其中六个区域包含属于该区域的基因 PE/PPE蛋白质家族在致病性分枝杆菌中特别丰富，已显示出来在分枝杆菌发病机理和调节关键先天免疫途径中的各种作用。但是，不已知PE/PPE蛋白与自噬途径有关。因此，该项目的目标是研究PE/PPE蛋白的一部分的作用和机制，并确定对天生和适应性免疫的分枝杆菌自噬降解。对M的知识增加。结核病感染引起的自噬为发现新的和有前途的治疗剂提供了机会针对结核病，以防止分枝杆菌感染和宿主内生存。另外，这项研究中产生的自噬突变体可能在有效的发展中具有重大应用安全且持续的结核病疫苗。