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
Mycobacterial species are important pathogens of both animals and
humans. Study into the lifestyles of these pathogens reveals extensive
parallels in their mechanisms of intracellular survival and persistence.
Our lab is dedicated to the study of pathogenic mycobacteria and the main
goals of the work in the lab fall into three discrete areas of research
addressing the interaction between the macrophage and the bacterium with
respect to the intracellular environment and the regulation of host cell
function.
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.
Graduate Fields
Dr. Russell is a member of the following Graduate Fields:
Comparative Biomedical Sciences
Immunology
Microbiology
Biochemistry, Molecular and Cell Biology
Lab Members
Robert Abramovitch, Postdoctoral Associate
Linda Bennet, Research Assistant
Mijeong Kim, Graduate Student
Georgiana Purdy, Postdoctoral Associate
Elizabeth Rhoades, Senior Research Associate
Kyle Rohde, Postdoctoral Associate
Kaori Sakamoto, Graduate Student
Ute Schwab, Research Associate
Michiei Sho, Graduate Student
Cassandra Streeter, Research Assistant
Brian VanderVen, Postdoctoral Associate
Robin Yates, Postdoctoral Associate
Related Links
Program in Infection and Pathobiology
Selected References
McKinney, J.D., Höner zu Bentrup, K., Munoz-Elias, E., Miczak, A.,
Chen, B., Chan, W-T., Swenson, D., Sacchettini, J.C., Jacobs, W.R. and
Russell, D.G. (2000) Persistence of Mycobacterium tuberculosis
in macrophages and mice requires the glyoxylate shunt enzyme isocitrate
lyase. Nature
406: 735-738.
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.
Alonso, A., Pethe, K., Russell, D.G., and Purdy, G.E. (2007) Lysosomal killing of Mycobacteria is mediated by ubiquitin-derived peptides and is enhanced by autophagy. Proc. Natl. Acad. Sci. USA. 104:6031-6036.
Rohde, K. H., Abramovitch, R. B. and Russell, D.G. (2007) The linkage between transcriptional profile and environmental stimuli during the invasion of macrophages by Mycobacterium tuberculosis. Cell, Host and Microbe. 2:352-364.
