Bacteria, like all organisms, must detect changes in their environment and respond appropriately. Failure in this regard places the organism at risk of elimination. A classic means by which bacteria sense and respond to their environment is via two component signal transduction (TCST) sytems that detect altered conditions and initiate an adaptive response to facilitate survival under the altered conditions. TCST systems are typically comprised of a sensory histidine kinase protein and a cognate response regulator. Bacterial species capable of growth in multiple environments have large numbers of TCST systems. Bacteria that are restricted to a pathogenic lifestyle possess fewer such systems. The restricted ecological niche of Helicobacter pylori, the etiologic agent of peptic ulcer disease and gastric cancer, suggests a limited repetoire of signals to which this pathogen must respond. However, there is one other mechanism used by H. pylori to adapt to ambient environmental conditions: the use of contingency genes. This pathogen has numerous contingency genes capable of phase variable expression due to high frequency mutation. By this mechanism, a subpopulation likely exists at all times that may be capable of surviving altered environmental conditions and is thus subject to selection. Our proposal examines a nexus of these two seemingly disparate means to survive environmental perturbations. The experiments described here will elaborate the relative contributions of signal transduction and phase variation in a system where a gene encoding a sensory histidine kinase is itself a contingency gene, capable of an unusual type of phase variation. Studies here will examine and quantify the ability of this TCST system to undergo phase variation and its subsequent effects on the adaptive response. Stabilizing mutations will be introduced to limit phase variation of the histidine kinase. Our studies will also shed light on the role of this system in the ability of H. pylori to adhere to the the gastric mucosa. Experiments proposed here will assess the role of a novel, geographically and ethnically restricted H. pylori DNA sequence, in the transcription of this signal transduction system. The ability of a TCST system to be the target of phase variation as well as to encode a gene product capable of initiating an adaptive response is a potential example of the efficiency of regulatory mechanisms employed by this gastric pathogen and may facilitate the decades long colonization of the human host. ? ?
