Helicobacter pylori is a major public health problem: at least 50% of the world population is persistently infected with this bacterium, including at least 30% of the United States population . Inflammation caused by H. pylori puts the infected population at increased risk for chronic gastritis, peptic ulcer disease, and gastric cancers, the second leading cause of cancer-related deaths in the world . Genetic variability in the bacterium explains, in part, this diverse disease outcome: patients are typically infected with more than one distinct strain [3,4,5] and population studies show that up to 25% of genes are variably present between strains [6,7]. My overall research goal is to investigate both mechanisms for generating diversity between H. pylori strains and the function variable genes. Genetic diversity is influenced by environmental factors, since the chronic host inflammatory response damages bacterial DNA . My studies show that DNA damage alters transcription of at least 25% of the H. pylori genome, and importantly induces genes required for natural competence, the ability to take up exogenous DNA. These findings led to the hypothesis that the DNA damage regulated gene set includes novel natural competence genes. Moreover, I find that exogenous DNA is a key transcriptional regulator: increased uptake of exogenous DNA triggers the same transcriptional program as DNA damage and natural competence is required to sustain transcription of the DNA damage program. The only source of DNA in these experiments was donor cells, so I hypothesized that a DNA damage regulated gene is required to obtain DNA from donor cells. Since lytic activities mediate competence induced predation in Streptococcus pneumoniae , I deleted a phage T4 lysozome homolog that is induced by DNA damage in H. pylori and found that the lys gene is required to obtain DNA from donor cells. The lys gene is present in 35% of H. pylori strains  and thus its role in promoting genetic exchange may contribute to variability in inflammation and progression to ulcer.
In Specific Aim 1, I propose biochemical and localization studies to understand the Lys mechanism of action as well as genetic study of two genes that form an operon with lys.
In Specific Aim 2, I will use our sequenced-defined library of transposon mutants to identify DNA damage regulated genes required to obtain DNA from donor cells and for natural competence. If the proposed aims are achieved, I will demonstrate that H. pylori has an active mechanism for obtaining DNA from donor cells and identify new components of several steps natural competence. These studies lay a foundation for a future R01, which will focus on mechanistic studies of natural competence and the role of genetic variation in persistent colonization and progression of inflammation to ulcer disease. These outcomes fit the mission of NIDDK to understand and treat the causes of ulcer disease.
Peptic Ulcers are not caused by stress, but rather infection with a bacterium called Helicobacter pylori, which also causes gastric cancer. Studying the bacterium will help us develop new drugs that will rid people of the infection and reduce greatly their risk of developing ulcers or stomach cancer.