Mycobacterium tuberculosis (Mtb) has adapted to survive a wide range of assaults—from our immuneresponse to antimicrobial therapeutics—intended to eradicate the organism. However, the molecular switchesthat enable Mtb to endure these stresses, slow replication or become dormant as a latent tuberculosis infection(LTBI) are not known. Emerging studies on the molecular underpinnings of stress survival in Escherichia coligenerally point to a major role for TA systems, which are operons comprising adjacent genes encoding twosmall (~10 kDa) proteins, a toxin and its cognate antitoxin that inhibits toxin activity in the TA protein-proteincomplex. Because the Mtb genome harbors an unusual abundance of TA systems (>80) relative to E. coli andother bacteria, their expression has been implicated in Mtb stress survival and/or the switch to the non-replicating persistent state characteristic of LTBI. While indirect evidence linking TA toxins to stress exposurein Mtb is accumulating, we do not have a clear understanding of the phenotypic switches triggered by thesestresses or their downstream effects. The goal of this R21 proposal is to test our hypothesis that some of theMtb MazF toxins may influence cell physiology by generating stress ribosomes that preferentially translateleaderless Mtb transcripts thought to encode proteins pivotal for stress survival and establishment of LTBI.
|Effective start/end date||12/1/16 → 11/30/18|
- National Institutes of Health (NIH)