M. tuberculosis (Mtb) is one of the leading causes of death worldwide and claims millions of lives annually. Approximately ~1.7 billion people worldwide are asymptomatically infected with the tubercle bacillus and constitute a major impediment to worldwide public health control measures. Previous work had shown that a point mutation (Arg ->His) in the 4.2 domain of RpoV, the principal sigma factor in 515 Mycobacterium bovis, is attenuating. Mice infected with Mtb?whiB3 showed significantly longer survival times than mice infected with the wild type Mtb. In addition, the lungs of Mtb?whiB3-infected mice appeared much less adversely affected. Recent studies have shown that WhiB3 is a 4Fe-4S cluster protein and initiates the metabolic switchover to the preferred in vivo carbon source, fatty acids. We hypothesize that WhiB3 is an intracellular redox sensor that maintains redox homeostasis. To better understand the mechanism of this physiological event, we will identify the WhiB3 amino acids necessary for effective iron-sulfur (Fe-S) reconstitution, and use electron paramagnetic resonance spectroscopy (EPR) to characterize these mutated proteins. We will use genome-wide expression profiling to examine the contribution of WhiB3 in maintaining redox homeostasis, and analyze the metabolite profile of Mtb?whiB3. These studies will characterize WhiB3 as a potential target for interventions. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain ~7 jobs.

Public Health Relevance

Mycobacterium tuberculosis (Mtb) is one of the most successful pathogens of mankind and is currently responsible for 2 million deaths worldwide each year. We have identified a series of TB sensors that sense host molecules that protects humans against infection and may be involved in persistence. Using several novel methods that we have invented, we will define how Mtb senses these protective host molecules, and how it relays the information.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076389-04
Application #
8318842
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Lacourciere, Karen A
Project Start
2009-07-22
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$326,329
Indirect Cost
$103,579
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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