Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis and infects one third of the world’s population. Due to the rise in multi-drug resistant strains of Mtb, it is critical to find pathways that are important for Mtb pathogenesis that may represent new targets for the development of improved therapies for this disease. One such target is the Pup-proteasome system of Mtb, which is important to cause lethal infections in mice. In an attempt to link proteasome function and Mtb pathogenesis, we identified a proteasomally regulated in copper repressor (RicR) regulon that is required for Mtb to defend against host-supplied copper (Cu). Deletion or disruption of individual RicR-regulated genes had no effect on virulence in mice. However, simultaneous inactivation of the RicR regulon highly attenuated bacterial growth in mice, indicating that the RicR regulon is required for the full virulence of Mtb. A follow-up study focused on the RicR-regulated socAB ( small ORF induced by copper A and B) locus discovered that disruption of socAB resulted in the reduced secretion of several substrates of two type VII (Esx) secretion systems, which reveals a potential link between copper homeostasis and protein secretion in Mtb. Our results suggest that copper homeostasis must be maintained during Mtb infection. Alternatively, copper may provide a cue for the appropriate release of virulence effectors that play a critical role at the host-Mtb interface.
|Advisor:||Darwin, Katerina H.|
|Commitee:||Belasco, Joel G., Philips, Jennifer A., Torres, Victor J.|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 78/01(E), Dissertation Abstracts International|
|Keywords:||Copper homeostasis, Mtb pathogenesis, Mycobacterium tuberculosis, Type VII secretion system|
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