R01AI177560

M. tuberculosis carbon metabolism during infection - The development of TB drugs benefits greatly from validation of novel drug targets in predictive animal models. M. tuberculosis (MTB) enzymes in central carbon metabolism are emerging as promising targets for drug development but have not been validated in animal models that recapitulate the diverse and heterogeneous environments MTB encounters in humans.

We propose to test the hypothesis that these heterogeneous environments result in airway, lung, and granuloma-dependent nutritional restrictions that, at times, make MTB dependent on both glycolysis and gluconeogenesis to establish and maintain infection in nonhuman primates and/or during paucibacillary infection in mice. We will infect NHPS with MTB mutants of two enzymes - PFK and PEPCK - that are required for glycolysis or gluconeogenesis, respectively.

We will use deletion mutants to determine whether these enzymes are required for the establishment of infection and use conditional knockdown mutants to investigate the enzymes' importance for growth and survival in different pathologies and for the progression of disease. We will furthermore evaluate these mutants in a relapse mouse model to test the hypothesis that the nutritional requirements during long-term persistence in mice, when the bacteria cannot be cultured in vitro, are different from those encountered during active growth and high titer chronic infection and ask whether they mimic environments encountered in NHPS.

This proposal builds on the experience of the multi-PI team in mycobacterial genetics, metabolism, and animal models, with the goal to dissect the carbon source requirements for MTB in the model system that is most similar to human MTB infection and disease.

Weill Medical College Of Cornell University

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 367% from $652,282 to $3,046,501.