Douglas E. Berg, Ph.D., the Alumni Professor of Molecular Biology and professor of genetics, has received a five-year $1.3 million grant from the National Institute of Allergy and Infectious Diseases and a five-year $1.6 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Berg studies Helicobacter pylori, the major cause of peptic ulcer disease and a risk factor for stomach cancer.
"This bacterium colonizes humans throughout the world," Berg said. "We want to understand how these infections can persist for years and years and to explore the genetic, physiologic and environmental factors that determine whether infection causes disease or simply persists without medical consequences, as it does in most infected people."
Berg's group will study resistance to metronidazole and clarithromycin, the two main therapeutic agents. In developing countries, these antibiotics are used widely to treat parasitic or gynecologic infections, a practice that favors the emergence of drug-resistant strains of H. pylori.
In the laboratory, the researchers have shown that inactivating the gene for a nitroreductase called rdxA makes H. pylori partly resistant to metronidazole. This enzyme normally converts metronidazole to a bactericidal compound. Berg's group has found that rdxA is nonfunctional in resistant strains from patients in many parts of the world.
The researchers have detected both laboratory and clinical strains of H. pylori that grow in the presence of even higher levels of metronidazole than the usual rdxA-deficient strains. "We suspect that these strains have mutations in additional genes -- perhaps genes for other nitro-reductases -- that can contribute quantitatively to metronidazole resistance," Berg said. The researchers now are looking for these genes. They also are studying mechanisms, including mutation or exchange of specific genes between strains, that confer antibiotic resistance to H. pylori or enable it to adapt to different human hosts.
The grant from the National Institute of Diabetes and Digestive and Kidney Diseases will support a study of H. pylori infection and gastroduodenal disease in Alaskan natives. This collaborative project will involve Alan Parkinson, Ph.D., and staff at the Arctic Investigations Unit in Anchorage, Alaska, which is operated by the Centers for Disease Control and Prevention. To look at H. pylori transmission patterns, the researchers will analyze the genetic fingerprints of H. pylori isolated from occupants of different native villages. Because of geographic isolation, the strains within a particular village might be closely related. And any differences might point to genes that allow the bacterium to thrive in a particular individual.
The researchers also will compare Alaskan strains of H. pylori with those isolated in other parts of the world. Genetic differences might explain the unique features, such as anemia, of peptic ulcer disease among Alaskan natives. This comparison also might help determine whether H. pylori arrived in Alaska from Asia many thousands of years ago with ancient ancestors of native peoples or whether, like many other microbial pathogens, it arrived in the New World with European conquerors and colonists during the past few hundred years.
