Genetic Analysis of Yersinia Enterocolitica Virulence

Infectious diseases continue to be a major worldwide problem, responsible for millions of deaths each year. There continues to be an urgent need to study the molecular basis of bacterial virulence, with the ultimate goal of identifying new therapeutic targets. Our lab primarily studies the human pathogen Yersinia enterocolitica. We are interested in characterizing mechanisms that are required to allow this organism to switch from free-living to disease-causing growth. Y. enterocolitica provides an excellent model system to gain insight into the ability of many different bacterial species to cause human disease. It is a close relative of the organism responsible for plague (Yersinia pestis), one of the most devastating diseases over the course of human history. In contrast to Y. pestis, Y. enterocolitica is primarily associated with gastrointestinal disease, although fatal systemic infections can occur. Y. enterocolitica is easily amenable to genetic analysis, has excellent infection models that mimic human disease, and shares common virulence mechanisms with many other bacterial pathogens.

Type III secretion systems (TTSS) are found in many different pathogenic bacteria. They deliver cytotoxic proteins inside host cells, disarming the ability of the host to defend itself. All TTSS, together with some other bacterial secretion systems, contain a component protein known as a secretin. We have found that the production of the secretin component of a Y. enterocolitica TTSS imposes a stress on the bacterial cell that triggers the expression of a group of genes known as the psp regulon. The Psp system responds to this stress and allows the bacterial cell to remain viable during TTSS production. As a result, the Psp system is essential for Y. enterocolitica virulence. The Psp system is widely conserved in many different pathogenic bacteria. This, together with the widespread occurrence of secretin-containing secretion systems, makes the study of the Psp system especially important. A major goal of our lab is to characterize the Y. enterocolitica Psp system and to understand its role in virulence. Specific projects include understanding signals that activate the Psp system (especially those that are present during host infection), studying the Psp regulatory and signal transduction mechanisms, investigating changes in the bacterial cell during conditions that activate the Psp system and how the Psp system responds to them.

In addition to the Psp system, we have a broad interest in the regulation of virulence genes. We have identified a previously uncharacterized regulatory protein (YtxR) that controls the expression of a putative toxin of unknown function along with a number of other genes encoding putative secreted or outer membrane proteins. We are currently attempting to understand the physiological role of the YtxR regulon.