This proposal will test the hypothesis that host-derived aldehydes are a critical component of host immunity against Mycobacterium tuberculosis. We will use bacterial and mouse genetics, biochemistry, immunology and cell biology experiments to test this hypothesis. We will identify bacterial mutants that are either more resistant or more sensitive than parental strains to various aldehydes in combination with nitric oxide, which appears to strongly synergize with several different aldehydes to kill bacteria. The isolation of these bacterial strains will allow us to test whether or not these pathways contribute to bacterial survival in mice. We will also investigate various host pathways from aerobic glycolysis to aldehyde dehydrogenase activity to assess the contribution of aldehyde products of these pathways in bacterial infection control. The outcome of our studies may ultimately help promote a clinical trial repurposing an FDA-approved drug for the treatment of tuberculosis and possibly other diseases.
The mechanisms used by the immune system to control bacterial infections is incompletely understood. We propose that metabolic intermediates, namely aldehydes, are used by the immune system to kill Mycobacterium tuberculosis and possibly other microbial agents. This proposal will identify sources of metabolic aldehydes that can control bacterial growth as well as bacterial pathways that affect susceptibility to aldehydes.
