- Research Interests
Research in my laboratory is dedicated to understanding the basis of infectious disease at molecular and cellular levels. We focus on mechanisms by which virulence factors produced by pathogenic microbes interact with host cell targets and thereby modulate host cell behavior during infection. We study these interactions in structural detail (i.e., at the level of atomic resolution through X-ray crystallography) in order to carry out precise biochemical, genetic, and cell biological experiments aimed at elucidating the mechanism of action of bacterial virulence factors in their cellular context.
Our studies focus on the initial interaction between a pathogen and a host cell, and how this interaction resolves as induction of intracellular entry or inhibition of phagocytic uptake. Induction of intracellular entry is exemplified by studies on Listeria monocytogenes. We are delving into how the L. monocytogenes protein InlB activates the host cell receptor tyrosine kinase Met (hepatocyte growth factor receptor, HGFR) to effect host cell invasion. Met is a proto-oncogene and therefore we hope to understand general rules of regulation of such crucial mediators of host cell growth through studies of InlB. Inhibition of phagocytic uptake is being pursued through studies on the mechanism of protein translocation into host cells by the Yersinia pseudotuberculosis type III secretion system as well as on antiopsonic surface proteins of Group A Streptococcus. In a broader sense, macromolecular recognition is at the heart of all these processes, and we are pursuing diversity-generating retroelements and the massively sequence variable protein repertoires that they produce in order to understand the general rules underlying specificity in molecular recognition.