Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells
Multiple distinct types of intracellular bacterial pathogens have been shown to alter the mechanics of their mammalian host cells to promote cell-to-cell spread. Conversely, host cells may respond by altering their own mechanical behavior to limit infection. We monitored epithelial cell monolayers sparsely infected with the intracellular bacterial pathogens Listeria monocytogenes or Rickettsia parkeri over the course of several days. Under conditions where these pathogens were able to trigger innate immune signaling through the NF-{kappa}B pathway and to use actin-based motility to spread non-lytically from cell to cell, domains of infected cells formed enormous three-dimensional mounds, where uninfected cells surrounding the infected cells became stiffer and actively moved toward the site of infection, collectively squeezing the softer and weaker infected cells up and ejecting them from the epithelial monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the focus, while mounded cells eventually underwent cell death. Cells in infected monolayers exhibited behavioral and molecular signatures of the epithelial to mesenchymal transition (EMT), such that coordinated forceful action by uninfected bystander cells actively eliminated large domains of infected cells, consistent with the hypothesis that this collective cell response represents an innate immune response.