Intracellular bacterial pathogens reprogram host cells to promote their survival, leading to devastating morbidity and mortality worldwide. Our research focuses on revealing how bacterial pathogens usurp host cell function to gain insights into both host cell biology and pathogenesis. In particular, we focus on how intracellular bacterial pathogens (e.g. Rickettsia parkeri and Listeria monocytogenes) hijack host machinery to move throughout tissues via cell-to-cell spread. This critical yet understudied virulence mechanism allows bacteria continued access to cytosolic nutrients and avoidance of humoral immune responses. However, moving through tissues without destroying cell integrity presents challenges, and we are investigating how bacteria spread by identifying the critical host and bacterial factors involved, and their mechanisms of action.
Several bacterial pathogens utilize cell-to-cell spread during their infectious life cycle. Our work focuses on two of these human pathogens: Rickettsia parkeri and Listeria monocytogenes. R. parkeri are obligate intracellular Gram-negative bacteria that cause spotted fever and are transmitted to humans by arthropod vectors. In contrast, L. monocytogenes are Gram-positive bacteria that cause listeriosis and meningitis, and are often ingested from contaminated food sources. Both pathogens can invade non-phagocytic 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.
Despite sharing similar life cycles, our work has revealed that the morphological and molecular details of spread differ between these two pathogens. Each pathogen requires a distinct set of host and bacterial proteins for spread, and utilize different force generating machinery to engage host intercellular junctions. This observation evokes several exciting questions with the potential to reveal fundamental biological insights. For example, how do bacteria target membrane junctions to induce protrusions and manipulate forces meant to maintain tissue integrity? How are host membrane-remodeling factors and endocytic pathways usurped during spread to shape and move the plasma membrane? Lastly, what bacterial factors are required and how do they reprogram host pathways during spread?
To tackle these important questions, we use a multidisciplinary approach combining cell biology, microbiology, genetics, biochemistry and biophysics to investigate the mechanisms of cell-to-cell spread. It is our belief that investigating the dynamic interplay between host and pathogen is critical to understanding mechanisms of virulence, and so we focus first on identifying the critical host and bacterial factors involved during spread using a variety of genetic screens. Then we use modern techniques to get a handle on their function. In the end, our goals are to dissect the pathways of spread to reveal important properties of pathogenesis, and use pathogens as tools to better understand host cell biology.