Mycobacterium tuberculosis (Mtb) has adapted to survive a wide range of assaults?from our immune response to antimicrobial therapeutics?intended to eradicate the organism. However, the molecular switches that 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 coli generally point to a major role for TA systems, which are operons comprising adjacent genes encoding two small (~10 kDa) proteins, a toxin and its cognate antitoxin that inhibits toxin activity in the TA protein-protein complex. Because the Mtb genome harbors an unusual abundance of TA systems (>80) relative to E. coli and other 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 exposure in Mtb is accumulating, we do not have a clear understanding of the phenotypic switches triggered by these stresses or their downstream effects. The goal of this R21 proposal is to test our hypothesis that some of the Mtb MazF toxins may influence cell physiology by generating stress ribosomes that preferentially translate leaderless Mtb transcripts thought to encode proteins pivotal for stress survival and establishment of LTBI.

Public Health Relevance

This proposal investigates how the bacterium that causes tuberculosis in humans, Mycobacterium tuberculosis, has the unique ability to evade being killed by our immune system and is able to persist for long periods of time in its host as a latent infection. Latent infections can be reactivated?especially in the immune compromised?to the highly contagious, active form of TB and accelerate spread of the disease. Therefore, it is important to understand how latent tuberculosis develops and how it becomes reactivated because globally the number of deaths caused by M. tuberculosis is now comparable to those caused by the HIV/AIDS virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI123859-02
Application #
9390454
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boyce, Jim P
Project Start
2016-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rbhs-Robert Wood Johnson Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code