The innate immune system that defends mammals from many Gram-negative bacteria is triggered when host cells sense the lipid A moiety of the bacterial cell wall lipopolysaccharide (LPS). The resulting inflammatory response then usually kills the bacteria. LPS-induced inflammation can also be harmful, however, and animals have numerous ways to limit its magnitude and duration. One important control mechanism is a highly conserved lipase, acyloxyacyl hydrolase (AOAH), that selectively removes from LPS the fatty acyl chains that are required for it to be sensed by MD-2--TLR4, the mammalian LPS receptor. Mice that have a disabling mutation in the AOAH gene respond to low doses of LPS by producing large quantities of antibodies and experiencing prolonged immunosuppression. If the LPS is given intravenously, they also develop striking enlargement of the liver. LPS that is not deacylated by AOAH remains stimulatory for weeks in vivo. We are now performing experiments to investigate the mechanisms by which LPS stimulation produces such impressive abnormalities in animals that cannot detoxify it.
RESEARCH INTERESTS
Detoxification of Bacterial Lipopolysaccharides
Physiologically-Responsive gene therapy for inflammatory diseases
Sepsis
RECENT PUBLICATIONS
M.Lu, M. Zhang, A. Takashima, et al. (R.S.Munford), "Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria" Nature Immunology, 6:989-994, October 2005
B. Shao, M. Lu, S.C. Katz,...R.S. Munford, "A host lipase detoxifies bacterial lipopolysaccharides in the liver and spleen" J. Biol. Chem., 282:13726-13735, May 2007
SIGNIFICANT PUBLICATIONS
R.S. Munford and A.W. Varley, "Shield as Signal: Lipopolysaccharides and the evolution of immunity to Gram-negative bacteria" PLoS Pathogens, 2:e67, June 2006
Munford, R.S., "Sensing Gram-negative Bacterial Lipopolysaccharides: a Human Disease Determinant?" Infect. Immun., 76:454-465, February 2008
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