Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially infected epithelial cells

• Published in: Developmental cell 2021-02, Vol.56 (4), p.443-460.e11
• Main Authors: Bastounis, Effie E., Serrano-Alcalde, Francisco, Radhakrishnan, Prathima, Engström, Patrik, Gómez-Benito, María J., Oswald, Mackenzi S., Yeh, Yi-Ting, Smith, Jason G., Welch, Matthew D., García-Aznar, José M., Theriot, Julie A.
• Format: Article
• Language: English
• Subjects: Actomyosin - metabolism; adhesions; Animals; Apoptosis; Biomechanical Phenomena; Cell Adhesion; Cell Competition; cell extrusion; Cell Line; cell mechanics; Computer Simulation; Dogs; epithelial cells; Epithelial Cells - immunology; Epithelial Cells - microbiology; Host-Pathogen Interactions; Humans; Immunity, Innate; infection focus; innate immunity; Intercellular Junctions - metabolism; Laser Therapy; Listeria monocytogenes; Listeria monocytogenes - physiology; Listeriosis - genetics; Listeriosis - immunology; Listeriosis - microbiology; Madin Darby Canine Kidney Cells; NF-kappa B - metabolism; Rickettsia parkeri; Signal Transduction; Time-Lapse Imaging; traction forces; Transcription, Genetic
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.01.012

Intracellular pathogens alter their host cells' mechanics to promote dissemination through tissues. Conversely, host cells may respond to the presence of pathogens by altering their mechanics to limit infection. Here, we monitored epithelial cell monolayers infected with intracellular bacterial pathogens, Listeria monocytogenes or Rickettsia parkeri, over days. Under conditions in which these pathogens trigger innate immune signaling through NF-κB and use actin-based motility to spread non-lytically intercellularly, we found that infected cell domains formed three-dimensional mounds. These mounds resulted from uninfected cells moving toward the infection site, collectively squeezing the softer and less contractile infected cells upward and ejecting them from the monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the infection focus, while extruded infected cells underwent cell death. Thus, the coordinated forceful action of uninfected cells actively eliminates large domains of infected cells, consistent with this collective cell response representing an innate immunity-driven process. [Display omitted] •Epithelial host cells form extruded mounds after infection with L. monocytogenes•3D mounds result from mechanical competition between infected and uninfected cells•Inhibition of cell-matrix and/or cell-cell forces inhibits infection mound formation•Innate immune signals control this mechanical competition that limits pathogen spread Bastounis et al. show that, during infection with the intracellular bacterial pathogen L. monocytogenes, large infected domains in epithelial cell monolayers extrude to form three-dimensional mounds due to the collective onslaught by their uninfected neighbors. This mechanical competition between uninfected and bacterially infected cells limits pathogen dissemination through the epithelium.