: Mycobacterium tuberculosis infects nearly one third of the world?s population and is a resurgent health hazard. In order to identify new targets for antimicrobial chemotherapies, it is critical to understand the molecular mechanisms of M tuberculosis pathogenesis. Cox et al. have recently performed a signature tagged mutagenesis to identify genes required for M. tuberculosis virulence in mice. One of the genes identified in this screen is mmpL4, which is predicted to encode a member of a family of large membrane proteins that act as lipid transporters. We have demonstrated that disruption of mmpL4 results in M. tuberculosis strains that are attenuated for growth in mice and that this growth defect is rescued in IFN-g -/- mice. Thus, we hypothesize that MmpL4 secretes a lipidic virulence factor into host cells that either inhibits IFN-g signaling or an IFN-g-regulated effector function. We propose to use biochemical methods to identify the molecule(s) secreted by MmpL4 and study the effects of this molecule on the immune response of the host. In order to understand the role of MmpL4 and its secretion substrate, we will compare the host-parasite interaction of wild-type and mmpL4 mutant bacteria using macrophage and mouse models of infection. We will determine whether MmpL4 is required for survival in activated macrophages or whether MmpL4 is required for proper IFN-g signaling. Finally, to identify other components of the MmpL4 pathway, we will disrupt genes in the putative mmpL4 operon and determine whether they are required for virulence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI050300-02
Application #
6511630
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
2002-07-01
Project End
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$38,320
Indirect Cost
Name
University of California San Francisco
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143