Douglas E. Berg, Ph.D.

RESEARCH INTEREST

We are studying the population genetic structure, evolution and mechanisms of colonization and virulence of Helicobacter pylori (Hp). This gastric pathogen chronically infects most people worldwide, usually beginning in early infancy, and is a major cause of peptic ulcers and gastric cancer. Three recent findings illustrate our approaches. 1. Population structure, evolution. Although Hp is among the most diverse of bacterial species, he has identified multiple DNA polymorphisms that distinguish strains from Asia and Europe. Strains from Native Peruvians match those of Spain, not Asia. This suggests that Hp was first brought to the Americas by European conquerors ~ 500 years ago, and that (contrary to widespread belief) Hp may not have been with humans "forever." These ideas will be tested in part by finding additional informative genetic markers, using strains from additional human populations, and experimental infections with animal models. 2. Specificity of infection. Analyses of H. pylori recovered after inoculation of mice with mixtures of two different "standard" H. pylori strains, SS1 and X47, demonstrated persistent mixed infection, and showed that one strain colonized the antrum (SS1), and the other the corpus (X47), preferentially. The strength of antrum-preference by strain SS1 increased with age of C57BL/6J host. In addition, SS1 far better able to colonize newborn (7 or 11 day old mice) than was X47, whereas 14 day old mice were equally susceptible to both strains. 3. Hierarchy of strengths of infection. Other sets of mouse colonizing Hp strains compete with each other far more directly than do SS1 and X47. Pairwise mixed infections allow strains to be arranged hierarchically. Tests of different inbred mouse lines (e.g., BALB/c, C57BL/6) shows that the "fitness" of a given Hp strain can depend critically on background host genotype. Future studies should clarify evolutionary forces affecting adaptation of individual H. pylori strains to variable and often hostile host environments. These are being coordinated with analyses of host responses to infection, in close collaboration with Drs. Shrikant Anant and Brian Dieckgraefe in the GI division. More generally, genetic analyses of quantitative traits in Hp and their (murine) hosts should increase our understanding of mechanisms in chronic infection, host responses and human disease.

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