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Lafuse, William
William P. Lafuse, Ph.D, is Professor of Molecular Virology, Immunology, and Medical Genetics. He joined the faculty in 1986. He is a member of CMIB and the Comprehensive Cancer Center. He is also a member of the Integrated Biomedical Science Graduate Program. The interaction of Mycobacteria (M. avium and M. tuberculosis) with mouse and human macrophages is being investigated in studies on the effect of mycobacteria infection on macrophage cell signaling, transcriptional activation, and macrophage iron metabolism. One area of research investigates pathways by which mycobacteria inhibit activation of macrophages by Interferon-gamma. Dr. Lafuse’s research has identified several mechanisms responsible for the inhibition of IFN-gamma induced gene expression. Current research is investigating the role of gene specific-transcription involving histone deacytlases. Our research has shown that inhibiting HDAC activity restores IFN-g induced gene response in mycobacteria infected macrophages. We also found that the expression of the mSin3A co-repressor, which recruits HDACs to promoters, is induced by mycobacteria infection and is present at the HLA-DR alpha promoter in mycobacteria infected human THP-1 cells. Another area research is effects of mycobacteria on iron metabolism in the macrophage. Iron is an essential nutrient for mycobacteria. Recent studies have identified iron transport proteins Nramp1, Nramp2, and Ferroportin 1 that are expressed by duodenal epithelial cells and are important in transporting dietary iron. The proteins are also expressed by macrophages, which also play an important role in maintaining iron homeostasis. Since the availability of iron is also important to the survival of intracellular pathogens, the expression of these proteins may also have important consequences on the outcome of pathogen-host interactions. Recent research has shown that hepcidin, a hormone with anti-microbial activity, which is synthesized by liver hepatocytes during the acute phase response to LPS, is a negative regulator of iron absorption by the duodenum and inhibits iron efflux from macrophages. Our research has shown that hepcidin mRNA is also produced by macrophages activated with M. tuberculosis and IFN-g. The propose of current research is to explore the expression of hepcidin and iron transport proteins Nramp1, Nramp2, and Ferroportin 1 during infection of mice and isolated macrophages with M. tuberculosis and to determine effect of hepcidin on iron metabolism and growth of M. tuberculosis in infected macrophages. Selected Publications Hussain, S., Zwilling, B.S. and Lafuse, W.P. Mycobacterium avium infection of mouse macrophages inhibits IFN-g JAK-STAT signaling and gene induction by down- regulation of the IFN-g receptor. J. Immunology 163:2041-9, 1999. Alvarez, G.R. Zwilling, B.S., and Lafuse, W.P. Mycobacterium avium Inhibition of IFN-g signaling in mouse macrophages: Toll-like receptor 2 stimulation increases expression of dominant-negative STAT1b by mRNA stabilization. J. Immunol.171:6766-6773, 2003. Curry, H., Alvarez, G.R., Zwilling, B.S., and Lafuse, W.P. Toll-like receptor 2 stimulation decreases IFN-g receptor expression in mouse RAW264.7 macrophages. J.Interferon Cytokine Res. 24:699-710, 2004. Wang, Y., Curry, H. M., Zwilling, B. S., and Lafuse, W.P. Mycobacteria inhibition of IFN-g induced HLA-DR gene expression by up-regulating histone deacetylation at the promoter region in human THP-1 monocytic cells. J. Immunol. 174: 5687-5694, 2005. Kuhn, D.E., Lafuse, W.P., and Zwilling, B.S. Iron transport into Mycobacterium avium-containing phagosomes from an Nramp1Gly169-transfected RAW264.7 macrophage cell line. J. Leukocyte Biol. 69:43-2001.
Lafuse Laboratory Personnel
Contact 2178 Graves |
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