Helicobacter pylori causes an inflammatory infiltrate in gastric mucosa that in about 10% of cases progresses to peptic ulcer disease or gastric cancer. Disease results from an interaction between strain-specific bacterial virulence genes and the particular host response, neither of which is well understood. Since experimental inoculation of rhesus macaques with H. pylori causes gastritis that closely mimics human infection, this model provides a unique opportunity to further our understanding of H. pylori pathogenesis. Rapid progress in genomics and gene expression technologies makes it possible to use the macaque model to study the H. pylori host-pathogen interaction by in vivo analysis of gene expression. We propose to extend our work in the rhesus model of H. pylori into an analysis of bacterial (Specific Aim 1) and host (Specific Aim 2) gene expression during experimental infection. Monkeys will be inoculated with a wild type H. pylori strain that reproducibly infects macaques, or with an isogenic mutant deleted in a specific gene implicated in H. pylori pathogenesis. Since pH is fundamental to host gastric physiology and to the niche in which H. pylori thrives, bacterial and host gene expression will also be examined after pharmacological manipulation of gastric pH. Quantitative real-time RT-PCR will be used to examine expression of H. pylori gene families that are likely involved in H. pylori-related disease or immune evasion. Gene expression in bacterial cells grown in vitro will be compared to that in cells isolated directly from infected monkeys. DNA microarray analysis will be used to study host expression of genes thought to be important in the fundamental processes of inflammation, proliferation, apoptosis, and cell signaling. Since the host immune response is increasingly recognized as a critical variable in the outcome of infection, we will also study host gene transcription after immunization with urease coupled with either CpG or alum adjuvant, in order to promote aTh1 or Th2 immune response, respectively (Specific Aim 3). These studies will provide a functional genomic understanding of the H. pylori host-pathogen relationship that may have implications for novel treatment or vaccine strategies. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042081-05A1
Application #
6573213
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Taylor, Katherine A
Project Start
1997-12-01
Project End
2007-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$362,702
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Martin, Miriam E; Dieter, Jacquelyn A; Luo, Zheng et al. (2012) Predicting the outcome of infectious diseases: variability among inbred mice as a new and powerful tool for biomarker discovery. MBio 3:e00199-12
Ta, Linda H; Hansen, Lori M; Sause, William E et al. (2012) Conserved transcriptional unit organization of the cag pathogenicity island among Helicobacter pylori strains. Front Cell Infect Microbiol 2:46
Perry, Sharon; de Jong, Bouke C; Solnick, Jay V et al. (2010) Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS One 5:e8804
Styer, Cathy M; Hansen, Lori M; Cooke, Cara L et al. (2010) Expression of the BabA adhesin during experimental infection with Helicobacter pylori. Infect Immun 78:1593-600
Cooke, Cara L; An, Hyun Joo; Kim, Jaehan et al. (2009) Modification of gastric mucin oligosaccharide expression in rhesus macaques after infection with Helicobacter pylori. Gastroenterology 137:1061-71, 1071.e1-8
Axsen, Wendy S; Styer, Cathy M; Solnick, Jay V (2009) Inhibition of heat shock protein expression by Helicobacter pylori. Microb Pathog 47:231-6
Raffatellu, Manuela; George, Michael D; Akiyama, Yuko et al. (2009) Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5:476-86
Hornsby, Michael J; Huff, Jennifer L; Kays, Robert J et al. (2008) Helicobacter pylori induces an antimicrobial response in rhesus macaques in a cag pathogenicity island-dependent manner. Gastroenterology 134:1049-57
Taylor, Jennifer M; Ziman, Melanie E; Canfield, Don R et al. (2008) Effects of a Th1- versus a Th2-biased immune response in protection against Helicobacter pylori challenge in mice. Microb Pathog 44:20-7
Amundsen, Susan K; Fero, Jutta; Hansen, Lori M et al. (2008) Helicobacter pylori AddAB helicase-nuclease and RecA promote recombination-related DNA repair and survival during stomach colonization. Mol Microbiol 69:994-1007

Showing the most recent 10 out of 31 publications