Uniformed Services University of the Health Sciences
Department of Microbiology and Immunology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3400
FAX: (301) 295-1545
Professor & Associate Dean of Graduate Education
Ph.D., University of Pennsylvania, 1976
The long term goals of the research in our laboratory are directed towards an understanding of the molecular and cellular mechanisms which regulate the host responses to Gram negative bacteria and the virulence factors of the bacteria which permit the organism's survival in the host. Through this integrated approach, development of more effective vaccines which are protective against Salmonella infections will be feasible.
One aspect of these studies is directed towards understanding Salmonella infections from a bacterial perspective, by delineating the initial steps in the invasion of the host by the Salmonella. Identification of the bacterial and environmental factors which regulate the invasive capacity of Salmonella will permit the development of methods to modulate the host response and thereby increase the resistance of the host to infection. Thus, these studies are centered on the identification of bacterial genes which permit Salmonella to enter human intestinal epithelial cells, utilizing gene fusion technology. Mutants of Salmonella that are defective in the adherence and also in the invasion of intestinal epithelial cells have been isolated. It is anticipated that these studies will lead to strategies in which adherence and invasion of these initial stages of the disease can be blocked and consequently result in the decrease in infection by these organisms.
A complementary project in the laboratory focuses on the intestinal epithelial cells of the host and their potential contribution to the pathogenesis of Salmonella infections. In these studies, induction of innate immune mechanisms in Salmonella-infected intestinal epithelial cells is being analyzed to determine the functional potential of these important early host cells in resistance to infection. One approach currently underway is to analyze the production of soluble mediators by the these cells, in the presence and absence of Salmonella. In addition, the effect(s) of these soluble mediators on other mucosal innate host cells is also under investigation. Understanding the role of these soluble mediators may permit targeting of these molecules as therapeutic interventions.
Thus, our laboratory permits the development of scientists who are interested in both sides of the host-parasite interaction scenario. It is hoped that such an approach will permit a more complete picture of the sequence of events, and the regulation thereof, after a bacterium infects its host. Possible projects include induction of innate immune mechanisms in Salmonella-infected intestinal epithelial cells; interactions of Salmonella-induced products of intestinal epithelial cells with other cells of the innate mucosal immune system; cell surface expression and secretion of Salmonella virulence gene products; identification, characterization and cloning of genes essential for Salmonella virulence.
artera, C. and E.S. Metcalf. 1993. Osmolarity and Growth Phase Overlap in the Regulation of Adherence and Invasion of Salmonella typhi to Human Intestinal Cells. Infection and Immunity61:3084-3089.
Weinstein, D.L., B. O'Neill, and E.S. Metcalf. 1997. Salmonella typhi Stimulation of Human Intestinal Epithelial Cells Induces Secretion of Epithelial Cell-Derived Interleukin-6. Infection and Immunity. 65:395-404.
Leclerc, G., C. Tartera, and E.S. Metcalf. 1998. Environmental Regulation of Salmonella typhi Invasion-Defective Mutants. Infect. Immun.66:682-691.
Weinstein, D.L., B. O'Neill, D.M. Hone, and E.S. Metcalf. 1998. Differential Early Interactions Between Salmonella typhi and Two Other Salmonella Pathogens with Intestinal Epithelial Cells. Infection and Immunity. 66:2310-2318.
Lo, W-F., H. Ong, E.S. Metcalf, and M.J. Soloski. 1999. Cytotoxic T Cell Responses to Gram-Negative Intracellular Bacterial Pathogens: Identification of bacterial-specific CD8+ T cells following infection with Salmonella and a major role for non-polymorphic Class Ib molecules. J. Immunol. 162:5398-5406
Lo, W-F., A. S. Woods, A. Declous, R.J. Cotter, E.S. Metcalf, and M.J. Soloski. 2000. Molecular Mimicry Mediated by MHC Class Ib Molecules Following Infection with Gram Negative Pathogens. Nature Medicine 6:215-8.