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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：
9815117
负责人：
Sunhee Lee
金额：
$ 56.54万
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 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9815117
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/TB 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 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 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.

摘要