Pathogenic bacteria must assemble and secrete virulence factors to interact with host tissues and cause disease. Gram-negative bacteria such as Escherichia coli face a special challenge in this regard, as they posses an outer membrane in addition to a cytoplasmic membrane and must secrete virulence factors across both these barriers. Our lab is interested in understanding virulence protein secretion by Gram-negative bacteria, particularly secretion across the outer membrane. The rising rate of antibiotic resistance among pathogenic bacteria has become a problem of major medical importance and bacterial protein secretion offers an attractive target for therapeutic intervention. A long-term goal of our laboratory is to apply information gained about virulence factor secretion towards the development of novel antimicrobial agents.

A focus of our research is pilus biogenesis by uropathogenic E. coli, the predominant causative agent of urinary tract infections. Pili are essential virulence organelles that radiate out from the bacterial cell surface, mediating recognition of and binding to host cells. In particular, we are interested in understanding the structure and function of an essential pilus assembly protein termed the usher. The usher is an outer membrane protein that directs pilus assembly and is required for secretion of pili to the cell surface. Using a combination of biochemistry, molecular biology and structural biology, we hope to uncover the molecular details of usher function and pilus biogenesis. Pilus biogenesis will also be used as a model system with which to understand the secretion of virulence factors across the outer membrane in general. In addition, pilus biogenesis provides an excellent model system for dissecting basic biological processes such as protein-protein interactions, protein targeting, and the ordered assembly of complex organelles.

A second focus of research in our laboratory is virulence protein secretion by Yersinia pestis and Francisella tularensis. Y. pestis and F. tularensis are the causative agents of plague and tularemia, respectively. Both of these bacteria are extremely virulent for humans when aerosolized and they are classified as Category A agents of bioterrorism as defined by the CDC. Genome sequence analysis of Y. pestis revealed the presence of numerous gene clusters related to the E. coli pilus biogenesis system. We are investigating the function of these genes and their roles in Y. pestis pathogenesis. The molecular basis for the virulence of F. tularensis is largely unknown. Preliminary genome analysis suggests that F. tularensis lacks secretion systems typically found in other bacterial pathogens. We are therefore interested in identifying and characterizing potential virulence factors of F. tularensis, focusing on surface and secreted proteins. Our expectation is that identification of virulence factors combined with a detailed understanding of virulence factor biogenesis will elucidate mechanisms of pathogenesis and provide targets for the design of novel reagents for the detection, analysis and treatment of Y. pestis and F. tularensis.