ERK activation waves coordinate mechanical cell competition leading to collective elimination via extrusion of bacterially infected cells
Lara Hundsdorfer,
Marie Muenkel,
Raul Aparicio-Yuste,
Julio Cesar Sanchez-Rendon,
Maria Jose Gomez-Benito,
Aylin Balmes,
Tilman E. Schäffer,
Ana Velic,
Yi-Ting Yeh,
Iordania Constantinou,
Kathryn Wright,
Gizem Özbaykal Güler,
Dominik Brokatzky,
Boris Maček,
Serge Mostowy,
Effie E. Bastounis
Affiliations
Lara Hundsdorfer
Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Marie Muenkel
Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Raul Aparicio-Yuste
Engineering Research Institute of Aragon (I3A), Department of Mechanical Engineering, University of Zaragoza, 50018 Zaragoza, Aragon, Spain
Julio Cesar Sanchez-Rendon
Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Maria Jose Gomez-Benito
Engineering Research Institute of Aragon (I3A), Department of Mechanical Engineering, University of Zaragoza, 50018 Zaragoza, Aragon, Spain
Aylin Balmes
Institute of Applied Physics, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Tilman E. Schäffer
Institute of Applied Physics, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Ana Velic
Proteome Center Tübingen, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Yi-Ting Yeh
Department of Mechanical Engineering, University of Washington, Seattle, WA 98195, USA
Iordania Constantinou
Institute of Microtechnology, Technische Universität Brauschweig, 38106 Braunschweig, Lower Saxony, Germany; Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig, 38106 Braunschweig, Lower Saxony, Germany
Kathryn Wright
Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Gizem Özbaykal Güler
Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Dominik Brokatzky
Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Boris Maček
Proteome Center Tübingen, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany
Serge Mostowy
Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Effie E. Bastounis
Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; Corresponding author
Summary: Epithelial cells respond to infection with the intracellular bacterial pathogen Listeria monocytogenes by altering their mechanics to promote collective infected cell extrusion (CICE) and limit infection spread across cell monolayers. However, the underlying biochemical pathways remain elusive. Here, using in vitro (epithelial monolayers) and in vivo (zebrafish larvae) models of infection with L. monocytogenes or Shigella flexneri, we explored the role of extracellular-signal-regulated kinase (ERK) activity waves in coordinating the mechanical battle between infected and surrounder uninfected cells that leads to CICE. We discovered that when ERK waves are suppressed, cells fail to exhibit alterations in cell shape and kinematics associated with CICE and behave more like quiescent uninfected monolayers. In particular, uninfected cells surrounding infection foci are unable to polarize, reinforce their monolayer stresses, and promote CICE. Our findings reveal that crosstalk between ERK waves and cell mechanics is key to collective elimination of large domains of infected cells.
