Research Overview
Our work focuses on the intracellular life cycles of two human pathogens: Rickettsia parkeri and Listeria monocytogenes. R. parkeri is an obligate intracellular Gram-negative bacterium that causes a mild spotted fever disease and is transmitted to humans by arthropod vectors. In contrast, L. monocytogenes is a facultative Gram-positive bacterium that cause listeriosis after ingestion of contaminated food sources. Both pathogens invade cells, enter the cytosol, and hijack host actin to promote actin-based motility. Motile bacteria then initiate cell-to-cell spread, a step-wise process during which bacteria propel themselves to the host cell membrane, form double-membrane protrusions into the recipient cell, and then become engulfed into a vesicle before escape to the recipient cell cytosol. These intricate, complex life cycles illustrate the different ways pathogens interact with their host and we are interested in elucidating the cellular and molecular mechanisms responsible. We investigate these mechanisms using an interdisciplinary approach combining cell biology, microbiology, genetics, biochemistry, and biophysics. In the end, our goals are to reveal important properties of pathogenesis and to use pathogens as tools to better understand host cell biology.
Cell-to-cell spread
Cell-to-cell spread is a critical yet understudied virulence mechanism that R. parkeri and L. monocytogenes use to promote tissue-wide dissemination. During cell-to-cell spread, bacteria remodel host cell-cell junctions into double-membrane protrusions that are engulfed by neighboring host cells. Intriguingly, these pathogens do not use the same strategies for spread, and we are investigating how these different mechanisms are regulated by examining the critical host and bacterial factors involved.
The study of cell-to-cell spread also allows us to ask questions about how host cell-cell junctions are remodeled by specific host pathways. Leveraging our microbial tools for cell biological studies, we aim to understand how mechanoresponsive, trafficking, and adhesion machinery respond to the dramatic shape and force changes during the process of bacterial cell-to-cell spread, which may shed light on how cells regulate the intercellular movement of other large cargo like organelles.
SECRETED EFFECTORS AND SECRETION Systems
Bacterial pathogens deploy proteins called secreted effectors into host cells that hijack host cell processes to promote infection. Notably, very little is known about the identity and function of the Rickettsia secretome or the machines responsible for secretion. We are combining our established functional-genetic approaches with biochemical tools like BONCAT to identify and study the role of secreted effectors during Rickettsia infection. We are also investigating how an anomalous Type 4 Secretion System drives effector delivery during infection.
Novel Regulators of Rickettsia Infection
We have pioneered efficient transposon mutagenesis and complementation studies for the investigation of Rickettsia parkeri pathogenesis. Our goal is to leverage these advances against new genetic, biochemical, and transcriptional tools we are developing in the lab to accelerate our understanding of regulators of Rickettsia infection. Through this work, we hope to gain a deeper, mechanistic understanding of how specific bacterial factors drive invasion, intracellular growth and survival, and cell-to-cell spread.
