Mechanisms of bacterial virulence: stress response and avoidance

Infectious diseases are 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 research uses genetics and biochemistry, along with cell culture and animal models of infection, to focus on two bacterial pathogens: Yersinia enterocolitica and Pseudomonas aeruginosa. Y. enterocolitica is primarily associated with gastrointestinal disease, although fatal systemic infections can occur. It is easily amenable to genetic analysis, has excellent infection models that mimic human disease, and shares common virulence mechanisms with many other bacterial pathogens. P. aeruginosa is one of the most common causes of hospital-acquired acute infections, which can be life threatening. It can also chronically infect the lungs of people with cystic fibrosis and is the leading contributor to their mortality.

Like many other pathogens, the virulence of Y. enterocolitica and P. aeruginosa depends on their ability to export toxic proteins into or onto host cells. This export requires the bacterial cell to insert a special molecule known as a “secretin” protein into its outer membrane. However, the production of these secretins can also injure the bacterium itself. Therefore, the organism must prevent or respond to this potential injury in order to successfully infect a host. Our work has revealed that Y. enterocolitica and P. aeruginosa have addressed this problem in very different ways.

Yersinia enterocolitica: In Y. enterocolitica, a highly specialized stress response system is required to tolerate cell injury caused by secretins. This is something called the Phage-shock-protein (Psp) system, which is essential for virulence in a mouse model of infection. Mutants with a defective Psp system are quickly killed if they synthesize a secretin protein, probably due to disruption of their cell envelope. We are interested in understanding signals that activate the Psp system, studying the Psp regulatory and signal transduction mechanisms, and investigating changes in bacterial physiology when the Psp system is active. The Psp system is conserved in many medically important bacteria, broadening the significance of this work.

Pseudomonas aeruginosa: P. aeruginosa is a prolific protein secretor, and has multiple secretin-containing export systems. However, it does not have a Psp system to deal with the potential for secretin-induced cell injury. We have recently begun to investigate why this is the case. Our work suggests that rather than having afunctional equivalent of the Psp stress response system, P. aeruginosa might actively prevent secretin-induced stress from occurring in the first place. We have isolated P. aeruginosa mutants that are hypersensitive to secretin protein production and are now characterizing the functions of the inactivated genes. One particularly interesting gene encodes a novel protein that appears to play an important role in ensuring that secretins function normally in P. aeruginosa.