UC Santa Cruz

The human gastric pathogen Helicobacter pylori relies upon chemotaxis during early infection, although the system appears dispensable during later stages of infection. This body of work describes efforts to characterize the signals interpreted by the cytoplasmic chemoreceptor TlpD and gain insight into the role the chemoreceptor plays during infection. Results of this work suggest that TlpD mediates chemotactic repellent responses to stimuli that evoke reactive oxygen species (ROS) formation in the cytoplasm and that these responses are involved in H. pylori colonization of gastric glands.

The first chapter serves as a review on chemotactic responses, and focuses on cytoplasmic chemoreceptors. This group of chemoreceptors are understudied relative to their transmembrane counterparts and are prevalent in both bacteria and archaea. An emphasis is placed on describing cytoplasmic chemoreceptors as a group, including likely ligand binding domains and their localization.

The ensuing chapters describes basic aspects of TlpD chemotactic responses and their relevance to colonization of the gastric epithelium. TlpD was found to sense and respond to stimuli that provoke cytoplasmic ROS production independently of transmembrane chemoreceptors, which include extracellular iron, hydrogen peroxide and superoxide generators. These findings suggest that the chemoreceptor senses and responds to a yet unknown signal generated by oxidative stress imparted by ROS, which likely involve labile cytoplasmic iron pools. We go on to describe colonization defects of a tlpD mutant, which appears to be connected to gastric gland colonization. The gastric gland colonization defects noted in wild type hosts for a tlpD mutant were rescued in hosts that were deficient in ROS production at the gastric epithelium. These results suggested that TlpD-mediated chemotactic responses to ROS were involved in H. pylori gastric gland colonization, and could be involved in the spread of the bacteria between glands in response to ROS production. Finally we discuss mechanistic issues concerning TlpD recognition of ROS.

Taken together these results have bolstered our basic understanding of TlpD signal transduction and the role of the chemoreceptor in host colonization.