B-261. Adaptation of Carbon Metabolism of Mycobacterium tuberculosis during Mouse Lung Infection

L. Shi1, C. D. Sohaskey2, R. J. North3, M. L. Gennaro1;
1Pub. Hlth. Res. Inst., Newark, NJ, 2Dept. of Veterans Affairs Med. Ctr., Long Beach, CA, 3Trudeau Inst., Saranac Lake, NY.

The intracellular pathogen Mycobacterium tuberculosis has evolved mechanisms of adaptation to the environment it finds in the host in order to establish a chronic infection. Work in vitro has shown that tubercle bacilli can utilize a wide range of carbon compounds, while it is established that lipids are probably the main carbon source during infection. In order to elucidate the adaptive changes of M. tuberculosis carbon metabolism in vivo we have utilized a mouse model of infection to assess by quantitative PCR the transcription profiles of M. tuberculosis genes involved in key central metabolic pathways and pathways that involve in fatty acid metabolism, triglyceride synthesis and synthesis of cell wall surface lipids. We find that M. tuberculosis genes involved in glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle are down regulated when expression of host immunity controls infection in the mouse lung. Downregulated are also genes responsible for the synthesis of phthiocerol acid dimycocerosate (PDIM), one of the major multimethyl-branched lipids located in mycobacterial cell wall. In contrast, M. tuberculosis genes that participate in glyoxylate shunt (icl), methylisocitrate cycle (gltA1), gluconeogenesis (pckA), fatty acid metabolism (fadD23, fadE5, kas and fas), and triglyceride synthesis (rv3130) are upregulated when bacterial infection is controlled. Taken together, these transcriptional changes indicate that tubercle bacilli divert carbon flux from pathways involved in generation of intermediates and energy required for bacterial growth to pathways that involved in cell wall modification and synthesis of storage compounds. For example, the potentially toxic propionyl CoA derived from the degradation of odd-chain fatty acids is no longer utilized during bacterial growth for the formation of PDIM, but it is instead anapleroticly metabolized through the methylcitrate cycle. We are currently investigating the regulation of this metabolic shift. We find that expression of methylcitrate synthase (gltA1) is regulated by the transcription factor encoded by rv1129c, which is adjacent to and divergently transcribed from rv1130 and rv1131 (gltA1).