Coordinate regulation of M. tuberculosis cell envelope composition during symbiosis

2002 new Scholar Award in gid

Tuberculosis remains a major cause of mortality worldwide and new antimicrobials that would shorten TB chemotherapy are badly needed. Our laboratory studies the pathogenesis of infection with Mycobacterium tuberculosis (Mtb) through a multidisciplinary approach that includes bacterial genetics, lipid biochemistry, and immunology. The long-term goal of these studies is to identify and understand bacterial molecules essential for Mtb pathogenesis that would be attractive therapeutic targets.

We are actively studying the relationship between Mtb pathogenesis and the chemical structure of the mycobacterial cell envelope. While the chemical structures of many cell envelope molecules have been defined in exquisite detail, their role in pathogenesis has been unclear. To understand the role of these unique chemical entities in pathogenesis of Mtb infection we have generated defined mutants of Mtb that lack specific compounds in the cell envelope. Specifically, we are examining the biosynthesis, pathogenetic role, and pathogenic function of the cyclopropane modification of mycolic acids, the major lipid in the Mtb cell envelope. We have found that perturbation of the cyclopropane content of the Mtb cell envelope through genetic deletion of individual cyclopropane synthetase genes alters the symbiotic behavior of Mtb in mouse models of bacterial persistence. These cyclopropane synthetase mutants invoke distinct inflammatory histopathology, suggesting a role for individual cyclopropyl residues on mycolic acids in modulating the host immune response. These studies suggest that the chemical diversity generated by the modification of mycolic acids with cyclopropyl groups is important for host-pathogen interactions. Through future analysis of Mtb mutants defective in cell envelope structures, we hope to understand how Mtb uses the chemical diversity of its cell envelope to modulate host-pathogen interactions to achieve microbial persistence. These studies may reveal novel targets for Mtb chemotherapy and may lead to fundamental insights into host recognition of mycobacterial lipid effector molecules.