Autophagy, an important 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 overcome the trafficking block imposed by Mycobacterium tuberculosis. Thus, induction of autophagy suppressed 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 inhibition of such virulence factors will allow us to understand the mechanisms by which autophagy affects the outcome of host-microbe interactions and the immune responses. Through gain-of-function screening of mycobacteria transformed with a cosmid library, we were able to identify two chromosomal regions responsible for manipulating mycobacterial infection- induced autophagy. We propose to study these two genomic regions and evaluate their role on mycobacterial survival and immunity. Increased knowledge of M. tuberculosis infection-induced autophagy may lead to new and promising therapeutics against tuberculosis. Additionally, the pro-autophagic mutants generated in this study may have significant application in the development of effective, safe and persistent TB vaccines.
We propose to study autophagy-regulating genes of Mycobacterium tuberculosis that enhances priming of adaptive immunity. The results of the study will be useful for improving the vaccine efficacy of BCG and developing noble TB vaccine candidates.
|Zullo, Alfred J; Jurcic Smith, Kristen L; Lee, Sunhee (2014) Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages. BMC Biochem 15:4|
|Zullo, Alfred J; Lee, Sunhee (2012) Mycobacterial induction of autophagy varies by species and occurs independently of mammalian target of rapamycin inhibition. J Biol Chem 287:12668-78|