- Bacterial pathogens hijack host intercellular communication machinery to promote spreadUC Berkeley
Cell-to-cell spread allows intracellular bacterial pathogens to move throughout host tissues, causing widespread infection. Rickettsia parkeri and Listeria monocytogenes spread by hijacking the host actin cytoskeleton for motility, which propels them to the plasma membrane, enabling the formation of membrane protrusions from the donor cell that are engulfed by a recipient cell. Although it has been assumed that spread is similar for both pathogens, I discovered surprising differences. In contrast with L. monocytogenes, R. parkeri generated short protrusions that often lacked actin comet tails and were resolved more quickly into vesicles in recipient cells. This suggested these pathogens employed divergent molecular mechanisms of spread. To identify these mechanisms, separate genetic screens were done to reveal important host or bacterial factors. First, I used RNAi screening to knock down host genes normally involved in cell-cell communication (e.g. cell adhesion, membrane remodeling, and endocytosis). This uncovered distinct sets of host factors, including different cadherin and caveolin isoforms that are selectively required by each pathogen. Second, bacterial factors that promote spread were identified using transposon mutagenesis of R. parkeri. One such factor was surface cell antigen 4 (Sca4), a secreted effector of R. parkeri that binds to the host cell adhesion protein vinculin. Sca4 promotes spread by inhibiting vinculin activity during mechanotransduction, which reduces intercellular tension and promotes protrusion engulfment. This work has uncovered significant differences in the features and molecular mechanisms of spread by different pathogens, and has highlighted that targeting host pathways of cell-cell communication may be key to promoting spread.
(Host : Alexei Korennykh / Contact: Anna Schmedel 8-5028)