Uniformed Services University of the Health Sciences
Department of Microbiology and Immunology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-1584
Lab: (301) 319-8022
Fax: (301) 295-3773
Investigation of the Host-Pathogen Interface using Helicobacter pylori
The process of human-bacterial interaction is, more often than not, a complex one that can range from benign symbiotic collaboration to a pathogenic association resulting in death of the host. My lab focuses on the complex interplay that occurs during pathogenic interactions, and how these interactions can lead to the development of disease. Currently, our studies are focused on the gastric pathogen Helicobacter pylori. Having no known environmental reservoir, H. pylori infects over half of the world?s population. Once colonized, it typically resides within the human host for the lifetime of the individual and can cause maladies that range in severity from gastritis, to ulcer disease, to the development of gastric carcinoma or mucosa-associated lymphoid tissue (MALT) lymphoma. Approximately 20% of those infected with H. pylori ultimately develop some form of overt clinical disease, and it is now accepted that disease outcome is determined by both bacterial and host genetic factors. The understanding of the process of disease onset and progression is still in its infancy, however.
Figure 1: False-colored electron micrograph of H. pylori.
Image courtesy of Lucinda Thompson, Stanford Medical School
Current work in the lab takes a two-pronged approach to investigating the process of H. pylori pathogenesis. First, since H. pylori colonizes and thrives within the human stomach, a site that is inhospitable to virtually all other microorganisms, the bacterium must be able to adapt to the stressful environment. In this organ, H. pylori experiences periods of extreme acidity, oxygen tension, iron limitation and a number of other environmental stresses. Since the microbe?s ability to sense and to respond to the environment being encountered is critical for colonization and long-term survival within the stomach, we have taken a genomic approach to define the transcriptional stress response of the bacterium to a number of different microenvironments. These studies are being extended by genetic and biochemical approaches to elucidate the role of individual genes in long-term survival and colonization of the bacterium.
Second, we are investigating the host changes brought about by interaction of H. pylori with eukaryotic cells. The bacterium is known to deliver a bacterial protein, CagA, to the host cell via a Type IV secretion apparatus. Once in the cell, CagA is tyrosine phosphorylated by members of the Src family of tyrosine kinases and subsequently binds to and deregulates the SHP2 phosphatase. Affected host cell signaling pathways past these are poorly understood, but it is known that the phosphorylation of CagA and subsequent deregulation of host cell signaling results in the induction of actin cytoskeletal rearrangements and morphological changes in infected gastric epithelial cells. In an effort to better understand H. pylori induced signaling events, we have defined host cell transcriptional changes that occur both in vitro (in tissue culture) and in vivo (in the murine gastric tract) upon interaction of the bacterium with host cells. Current studies are further investigating the roles of the effected genes using a biochemical and cell biological approach and attempting to define their expression levels in gastric biopsy samples from patients suffering from gastric cancer.
Figure 2: Electron micrograph showing H. pylori attached to polarized T84 cells.
Image courtesy of Sahar El-Etr, Stanford Medical School.