Pathogenic bacteria must assemble and secrete virulence factors to interact with host cells and cause disease. Our laboratory is interested in understanding mechanisms of virulence protein secretion by bacteria and the functions of secreted virulence factors within the host. Our long-term goal is to combine the identification of virulence factors with a detailed understanding of virulence factor biogenesis to elucidate mechanisms of pathogenesis and develop targets for the design of novel antimicrobial agents.
One focus of our research is pilus biogenesis by uropathogenic Escherichia coli, the predominant causative agent of urinary tract infections. Pili are hairlike, adhesive organelles that radiate out from the bacterial surface and are critical for adhesion to host cells. The pili expressed by uropathogenic E. coli are polymers composed of thousands of subunit proteins, each of which must be assembled in a defined order on the bacterial surface. This is accomplished by a conserved secretion system termed the chaperone/usher pathway. We are using a combination of molecular, biochemical, and structural approaches to uncover the molecular details of pilus biogenesis by the chaperone/usher pathway, with an emphasis on events occurring at the bacterial outer membrane.
A second focus of our research is virulence mechanisms of Francisella tularensis and Yersinia pestis. F. tularensis and Y. pestis are the causative agents of tularemia and plague, respectively. Both of these bacteria are highly virulent for humans, particularly when inhaled, and have the potential to be misused as biological weapons. Genome sequencing of Y. pestis revealed the presence of multiple gene clusters related to the chaperone/usher pilus assembly pathway. We are investigating the function of these gene clusters and their roles in Y. pestis pathogenesis. The molecular basis for the high infectivity and virulence of F. tularensis is just beginning to be understood. We have identified two secretion systems important for the virulence of F. tularensis: the pil genes, responsible for both pilus assembly and protein secretion, and TolC, involved in both multidrug efflux and protein secretion. In addition, we have shown that F. tularensis produces outer membrane vesicles and novel, tubular extensions of the outer membrane. These vesicles and tubes contain known F. tularensis virulence factors and we hypothesize that they mediate delivery of the virulence factors to host cells. We are dissecting the mechanism of action of these different Francisella secretion systems and are continuing to identify and characterize additional factors important for F. tularensis pathogenesis.