"In general my research interests focus on the interaction between intracellular pathogens and their host cell. More specifically my laboratory has been studying the nature of the interaction between macrophages and the bacterial pathogen Mycobacterium. Intriguingly, the macrophage acts as both host cell and effector cell in the eradication of these infections. Mycobacterium spp. remain intravacuolar throughout their intracellular infection. However in contrast to the normal pathway of phagosome maturation, Mycobacterium spp. maintain their vacuoles as a non-acidic compartments that do not fuse with lysosomes. Despite this mycobacterial vacuoles remain highly dynamic, accessible to both sphingolipids and transferrin from the cell surface. Pathogenic Mycobacterium species have evolved a strategy to arrest the normal maturation process of their phagosome. The elucidation of this process is being studied through analysis of host cell kinases responsible for the differentiation of maturing endosomes, and through the isolation of transposon-mutagenized Mycobacterium tuberculosis that are defective in arresting phagosome maturation.

Upon activation of the host macrophage with cytokines such as interferon-g, the vacuoles containing the bacteria acidify and are capable of fusing with lysosomes. This transition takes place even if the bacteria are still fully viable. Recent work in the lab has shown that this alteration in environment leads to a switch in bacterial metabolism. Under such conditions the bacteria need to mobilize the glyoxylate pathway for catabolism of fatty acids in order to sustain an infection in an immune competent host. Bacteria that have had their isocitrate lyase gene deleted establish, but cannot sustain, infection in both mice or macrophages activated in culture. Our ongoing studies involve targeting other enzymes in this carbon-acquisition pathway, screening for inhibitors of isocitrate lyase and malate synthase as possible lead compounds for drug development, and identification of the sensor/effector pathways that enable the bacterium to detect the environmental shift and change their pattern of gene expression.

Our interest also extends to the environment surrounding the infected macrophages. All Mycobacterium spp. induce granulomas at site of infection. These granulomas serve to restrict spread of infection, yet they also provide a relatively safe haven for the bacterium because they retain the cellular immune response at a distance from potential effector macrophages. Cell wall lipids that are actively released by the bacteria are potent stimulators of granuloma formation and, when added to polystyrene spheres and inoculated into mice, they induce a granulomatous reaction. In an immunized recipient this tissue development is enhanced markedly and we are using this model to dissect out the immune processes responsible for building the granuloma."