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, to slow replication or to become dormant as a latent tuberculosis infection are not known. Emerging studies on the molecular underpinnings of stress survival point to the activity of the toxin component of Mtb toxin-antitoxin systems in mediating the switch to the non-replicating persistent state characteristic of latent tuberculosis infection. This R21 proposal outlines experiments that test the novel hypothesis that a subset of these toxins do not globally inhibit translation but instead are highly specific tRNases that trigger a combination of ribosome frameshifting and ribosome stalling to surgically manipulate the Mtb proteome as a means to alter the physiology and/or metabolism of this pathogen.

Public Health Relevance

This proposal investigates how the bacterium that causes tuberculosis (TB) 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 now exceeds 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 #
1R21AI151574-01
Application #
9957759
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lacourciere, Karen A
Project Start
2020-02-21
Project End
2022-01-31
Budget Start
2020-02-21
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
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