Mucosal Immunology Laboratory, Director: W. Allan Walker
Summary of Research
My laboratory studies innate host defenses to gastrointestinal infection, using Salmonella typhimurium as a model bacterial pathogen. S. typhimurium is an important cause of acute gastroenteritis in humans and provokes a vigorous inflammatory response in the intestine. Although self-limited in most individuals, this disease can be potentially life threatening in the very young, the elderly and the immunocompromised, and is a significant cause of morbidity at all ages. Other types of Salmonella, such as S. typhi and S. paratyphi, cause a systemic febrile illness, typhoid fever, which is responsible for a large number of deaths in the developing world. In this disease, the organism survives for extended periods within host macrophages in the liver, spleen and bone marrow.
One of the projects in the laboratory is directed at elucidating the molecular details of the intestinal inflammatory response to Salmonella. We have shown recently that interferon gamma (IFN) plays an important role in regulating the Salmonella-induced inflammatory response in the intestine. Our observation that this function is developmentally regulated may explain why very young children have more difficulty in controlling the infection. We are currently carrying out experiments to investigate the role of some of the IFN-regulated genes in intestinal inflammation.
The other important question that we are addressing relates to the mechanisms involved in the intracellular survival of Salmonella. Specifically, we are interested in understanding how the organism adapts to its intracellular niche, and conversely, how the host attempts to restrict the growth of the pathogen. We have recently started to analyze the role of iron metabolism in these processes. In collaboration with Dr. Marianne Wessling-Resnick at the Harvard School of Public Health, we have found that changes in expression or function of the macrophage iron transporter ferroportin have significant effects on intracellular growth of Salmonella. We are continuing these studies to clarify the mechanisms of iron acquisition by the intracellular bacteria.
It is our hope that these investigations will shed light on important aspects of innate immune mechanisms and Salmonella pathogenesis, and that the information provided by our studies will be useful in devising new ways to treat and prevent the diseases caused by this organism and other enteric pathogens.
Selected Recent Publications
- Li, Q. and Cherayil, B.J. The role of Toll-like receptor 4 in macrophage activation and tolerance during Salmonella infection. Infect. Immun. 2003; 71: 4873-4882.
- Cherayil, B.J. How not to get bugged by bugs: mechanisms of cellular tolerance to microorganisms. Curr. Opin. Gastroenterol.. 2003; 19: 572-577.
- Claud, E.C., Lu, L., Anton, P., Savidge, T., Walker, W.A. and Cherayil, B.J. Developmentally-regulated IB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc. Natl. Acad. Sci. USA. 2004; 101: 7404-7408.
- Huang, F.C., Werne, A., Li, Q., Galyov, E.E., Walker, W.A., and Cherayil, B.J. Cooperative interactions between flagellin and SopE2 in the epithelial IL-8 response to Salmonella. Infect. Immun. 2004; 72: 5052-5062.
- Rhee, S.J., Walker, W.A., and Cherayil, B.J. Developmentally-regulated intestinal expression of IFN and its target genes and the age-specific response to enteric Salmonella infection. J. Immunol. 2005; 175: 1127-1136.
- Chlosta, S., Fishman, D.S., Harrington, L., Johnson, E.E., Knutson, MD, Wessling-Resnick, M., and Cherayil, B.J. The iron efflux protein ferroportin regulates the intracellular growth of Salmonella. Infect. Immun. 2006; 74: 3065-3067.
Contact Information
Phone: 617-726-4170
Fax: 617-726-4172
E-mail: cherayil@helix.mgh.harvard.edu
