|
|
David G. Russell
Dr. Russell assumed his position as Professor and Chair of the Department of Microbiology and Immunology in July 2000. His previous experience was as professor in the Department of Molecular Microbiology at Washington University School of Medicine, in St. Louis where he had worked since 1990. He received a B.Sc. degree in Zoology from St. Andrews University in Scotland in 1979 and was awarded a Ph.D. from Imperial College, London University in 1982. He has held positions at the University of Kent, the Max-Planck-Institute in Tuebingen, and NYU School of Medicine prior to moving to St. Louis. His research program has maintained continuous funding from the National Institutes of Health for research into the biology of the intramacrophage pathogens Mycobacterium and Leishmania. Research Interests / Graduate Fields / Lab Members / Related Links / Selected References Research Interests Firstly, the intracellular vacuole in which the bacillus resides exhibits arrested maturation and fails to differentiate into acidic, hydrolytically-active lysosomes. We are actively pursuing both the mechanism and consequences of this unusual strategy for intracellular survival. If the macrophage is activated, the host cell can overcome this blockage and deliver the bacterium to a lysosomal compartment, culminating ultimately in the death of the bacterium. We are studying the effects that macrophage activation has on intracellular trafficking using new assays that quantify phagosome/lysosome fusion and the hydrolytic capacity of the evolving environment within the lumen of the vacuole. These studies address basic questions with respect to the regulation and progression of phagosome maturation. Secondly, studies on carbon source utilization by intracellular Mycobacterium demonstrate that the bacterium needs to metabolize fatty acids when the course of infection changes from the acute phase to the chronic phase, and the bacterium transitions into a more vegetative growth cycle. We are exploiting genetic approaches to identify genes involved in uptake and breakdown of host fatty acids. The enzymes of this pathway are being pursued as drug targets. In pursuit of this goal we have developed microarray approaches to define the metabolic status of the bacterium in its intracellular niches at differing levels of macrophage activation. Finally, mycobacterial infections induce formation of granulomas that prevent spread of infection yet in turn provide a safe haven for the bacterium because they retain the lymphocytes of the host at a distance from the infected macrophages. The bacterial cell wall constituents are released by intracellular organisms and appear to promote formation of the granuloma. We have developed an in vitro model system to determine the cytokine and chemokine pathways activated in formation and maintenance of this structure. The role(s) of these lipids in guiding the progress of the infection is being studied and the findings of this in vitro model are being examined in the context of human tuberculosis. Dr. Russell is a member of the following Graduate Fields:
Lab Members
Program in Infection & Pathobiology
Selected References Pethe, K. Swenson, L.D., Alonso, S., Anderson, J., Wang, C., and Russell, D.G. (2004) Isolation of Mycobacterium tuberculosis mutants defective in the arrest of phagosome maturation. Proc. Natl. Acad. Sci. USA. 101:13642-13647. Geisel, R.E., Russell, D.G., and Rhoades, E.R. (2005) In vivo activity of released mycobacterial cell wall lipids is due principally to trehalose mycolates. J. Immunol. 174:5007-5015. Yates, R.M. and Russell, D.G. (2005) Phagosome maturation proceeds independently of stimulation of Toll-like receptors 2 and 4. Immunity 23:409-417. Russell, D. G. (2007) Who puts the tubercle in tuberculosis? Nature Reviews Microbiology 5: 39-47 Yates, R.M., Hermetter, A., Taylor, G.A., and Russell, D.G. (2007) Macrophage
activation down-regulates the degradative capacity of the phagosome. Traffic
8:241-250.
MicroImm
Home Questions or
Comments? |
