Microbes that are able to persist in their hosts are subject to different selective pressures than are those that transiently infect, and either kill their host or are themselves eliminated. In mammals, the gastrointestinal and genital tracts and skin represent biological niches that usually are populated by colonizing bacteria. We have been interested in bacteria of the Campylobacter and Helicobacter species, highly diverse organisms that live in the mucus layer overlying the mucosal epithelium of mammals, including humans. H. pylori colonization increases risk for development of peptic ulcer disease and gastric adenocarcinoma. Conversely, its presence appears to protect against certain diseases of the esophagus. The focus in my laboratory is to explore the biology of H. pylori colonization and the nature of the interactions that lead to (or protect from) disease. Several avenues are being approached. We are examining the variation in particular oligosaccharide (Lewis) antigens on the H. pylori cell surface and the nature of the host forces that select for cells of particular phenotypes. Disciplines involved include molecular biology, genetics, and mathematics. We are using transgenic and knockout mice to test hypotheses related to both host factors and bacterial evolution. Other projects relate to restriction-modification systems that act as barriers to horizontal gene transfer, and to a metastable "pathogenicity island" in the H. pylori genome (cag island). A third area of work relates to recombination, endogenous mutation, and DNA repair to understand their roles and regulation in the generation of diversity.


Another focus of our work is Campylobacter fetus, a pathogen of animals and humans. C. fetus cells are covered with S-layer proteins that allow the organisms to escape complement-mediated lysis, and that undergo antigenic variation. Exploring the molecular basis of variation, we have found that the S-layer proteins are encoded by a family of sapA homologs tightly clustered on the chromosome, and that a high frequency DNA inversion plays a critical role in variation. The inversion shows elements of both site-specific and homologous recombination. This is a highly tractable system to examine DNA recombination mechanisms, as well as for structure-function analysis of protein-carbohydrate (LPS) interactions, and the structural basis of antigenicity.


Study of these persistent colonizers has led to explorations of the bacteria (and fungi) normally inhabiting stomach, esophagus and skin using 16SrRNA approaches.