Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world's population. As an intracellular pathogen adapted to long-term survival, M. tuberculosis has evolved mechanisms to resist killing by host antimicrobial pathways. Targeting those resistance mechanisms has recently emerged as a powerful new approach to treating M. tuberculosis infection by enhancing the host's ability to eradicate the bacteria. However, the full repertoire of mycobacterial resistance genes is not known, and expanding this knowledge base provides additional avenues for the development of new drugs. We demonstrated the M. tuberculosis induces an enzyme, heme oxygenase, that produces carbon monoxide (CO) gas, and that M. tuberculosis both adapts to and resists killing by CO. We hypothesized that M. tuberculosis evolved genes for CO resistance, and our preliminary data indicate that M. tuberculosis encodes one such gene that when mutated results in attenuated virulence. We will apply metabolomic, transcriptomic, proteomic, and biochemical approaches to determine the function of the newly discovered CO resistance protein. Thus, in the proposed research we will (1) identify the molecular mechanism of CO resistance, (2) determine the interacting partners of the CO resistance gene and their role in CO resistance and (3) characterize the pathogenic effects of mutants in the CO resistance gene and its interacting partners. The proposed work will extend the current knowledge on M. tuberculosis's antimicrobial resistance mechanisms and reveal a novel microbial survival strategy.
Tuberculosis is a major human pathogen, accounting for significant morbidity and mortality worldwide. Work outlined in this proposal will investigate a novel mechanism that allows M. tuberculosis to survive and persist within humans. We expect that this work will help identify new potential drug targets for the treatment of tuberculosis.
The mechanisms used by Mycobacterium tuberculosis to survive within the host are incompletely understood. We propose to study how M. tuberculosis survives exposure to carbon monoxide, a toxic gas produced by host macrophages, focusing on the mycobacterial gene Rv1829 that we identified in a screen for CO resistance mutants. This approach is novel because it represents the first description of a CO resistance gene in a major human pathogen.
|Franco, Luis H; Nair, Vidhya R; Scharn, Caitlyn R et al. (2017) The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. Cell Host Microbe 21:59-72|
|Shin, Hyun-Jin; Franco, Luis H; Nair, Vidhya R et al. (2017) A baculovirus-conjugated mimotope vaccine targeting Mycobacterium tuberculosis lipoarabinomannan. PLoS One 12:e0185945|
|Nair, Vidhya R; Franco, Luis H; Zacharia, Vineetha M et al. (2016) Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection. Cell Rep 16:1253-1258|
|Scharn, Caitlyn R; Collins, Angela C; Nair, Vidhya R et al. (2016) Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection. J Immunol 196:4641-9|
|Shiloh, Michael U (2016) Mechanisms of mycobacterial transmission: how does Mycobacterium tuberculosis enter and escape from the human host. Future Microbiol 11:1503-1506|
|Collins, Angela C; Cai, Haocheng; Li, Tuo et al. (2015) Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis. Cell Host Microbe 17:820-8|
|Stamm, Chelsea E; Collins, Angela C; Shiloh, Michael U (2015) Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol Rev 264:204-19|
|Prokesch, Bonnie C; Shiloh, Michael U (2014) EBV-driven HIV-associated diffuse large B-cell lymphoma causing profound lactic acidosis. Blood 124:842|
|Manzanillo, Paolo S; Ayres, Janelle S; Watson, Robert O et al. (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512-6|
|Sampaio, Elizabeth P; Hsu, Amy P; Pechacek, Joseph et al. (2013) Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol 131:1624-34|
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