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 the assembly of pili (also known as fimbriae) 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 initiating and sustaining infection. 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. We are exploiting this knowledge for the identification and development of small molecule ‘pilicides’ as alternatives to traditional antibiotics.

A second focus of our research is on virulence mechanisms of Francisella tularensis. F. tularensis is a Gram-negative, intracellular pathogen that causes the zoonotic disease tularemia. F. tularensis is highly virulent for humans, particularly when inhaled, and has the potential to be misused as a biological weapon. The molecular basis for the high infectivity and intracellular pathogenesis of F. tularensis is not well understood. We have identified several secretion systems important for Francisella virulence, including the pil genes, which function in both pilus assembly and protein secretion, and TolC, involved in multidrug efflux and virulence factor export. In addition, we have shown that F. tularensis produces outer membrane vesicles and novel, tubular extensions of its cell surface. These vesicles and tubes contain known F. tularensis virulence factors and are produced during infection of host cells. We are using a multidisciplinary approach, including cell culture and mouse infection models, to dissect the mechanism of action of these Francisella secretion systems and how they function to promote intracellular pathogenesis and subvert host immune responses during infection.