Research Abstract:
We study Helicobacter pylori (Hp), a genetically diverse species that chronically infects the gastric mucosa of billions of people worldwide. It constitutes a major cause of peptic ulcers and gastric cancer, even though most infections are asymptomatic. Infections seem poised on a “knife edge”, always provoking some inflammation, which provides nutrients for bacterial growth while being insufficient for pathogen clearance. Three projects listed below illustrate current research directions. 1) Hp population genetics. Analysis of housekeeping gene sequences of Hp from different human populations showed that East Asian and Spanish strains are distinct, and that strains of urban Peruvian Amerindians are mostly Spanish-like whereas strains from a remote Amazonian population are Asian-like. Perhaps Hp brought to the Americas by European conquerors were more robust than ancestral Amerindian strains and outcompete them during mixed infection. To help examine factors that may be responsible for differences in fitness in human populations we are sequencing the genome of an Hp strain from a remote Peruvian Amazon population that is quite unlike the strains that predominate in urban Peruvians. 2) Evolution in real time. We are finding mutations in multiple genes that allow stepwise emergence of high level metronidazole (Mtz) resistance, using new “resequencing” and classical test cross and functional analysis methods. Many of these mutations diminish the ability of cells to chemically reduce Mtz from prodrug to bactericidal agent. Some are additive and others are epistatic in their effects, and some of them affect resistance phenotypes only in certain bacterial contexts. Taken together, these analyses give us new insights into flexibility and parallelism in the evolution of metabolic networks. A final set of resistance mutations alter Hp’s novel “Fur” iron and pH responsive regulatory protein; and conversely, certain other fur mutations dramatically increase susceptibility to Mtz. These analyses should give valuable insights into structure and function of a novel regulatory protein, and into how one protein can impose direct control over several different regulatory circuits in a physiologically responsive manner. The phenomenon of high level drug resistance can serve as a general model for analyses of complex and important genetic traits with implications for the new discipline of “systems biology”.
Selected Publications:
Ogura M, Perez JC, Mittl PRE, Lee H-K, Dailide G, Tan S, Ito Y, Secka O, Dailidiene D, Putty, K, Berg DE, Kalia A. Helicobacter pylori evolution: Lineage specific adaptations in homologs of eukaryotic Sel1-like genes. PLOS Computational Biology 2007 3(8) e151 (pp1-13).
Dailidiene D, Dailide G, Kersulyte D, and Berg DE. Contraselectable streptomycin susceptibility determinant for genetic manipulation and analysis of Helicobacter pylori. Appl Env Microbiol 2006 72:5908-5914.
Albert TJ, Dailidiene D, Dailide G, Norton JE, Kalia A, Richmond TA, Molla M, Singh J, Green RD, Berg DE. Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori. Nature Methods 2005 2:951-953.
Tan S, Fraley CD, Zhang M, Dailidiene D, Kornberg A. and Berg DE. Diverse phenotypes resulting from polyphosphate kinase gene (ppk1) inactivation in different strains of Helicobacter pylori. J Bacteriol 2005 187:7687-7695.
Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikström S, Sjöström R, Lindén S, Lundberg C, Bäckström A, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatiño B, Gilman RH, Gerhard M, Alarcon T, López-Brea M, Nakazawa T, Fox JG, Correa, P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE, Borén T. Functional adaptation of the Helicobacter pylori ABO blood-group antigen-binding adhesin. Science 2004 305:519-522.
Last Updated: 08/05/2008 |