Control of Host Mechanics by a Bacterial Pathogen and Functional Impact

Introduction

Mammalian cells sense and exert forces on their environment, and their responses to mechanical signals regulate their growth, motility, and behavior within tissues. However, little is known about the forces at play during microbial infections, and their impact on tissue homeostasis and disease progression.

Background

I recently found that binding of the extracellular bacterium Neisseria meningitidis (Nm) on the endothelium leads to the generation of large traction forces on the extracellular matrix. This is due to the formation of a new structure, that I called ancreopodia, linking the bacterial colony on the apical side of the host cell to the basal side and underlying substrate. I hence hypothesize that Nm induces long-range force transmission throughout the infected cells, leading to alterations in tissue function.

Project Objectives

In this project, I propose to dissect how host cell mechanics is affected by Nm infection, and how mechanical forces globally impact tissue barrier physiology in epithelia and endothelia. By developing quantitative tools to directly measure forces while imaging host cells during infection, both in vitro using 2D and 3D models of tissue barrier with increasing complexity and in vivo, I will:

1. Identify the key molecular mechanisms involved in host cell structural remodeling and their regulation in space and time.
2. Characterize the mechanics of the infected host tissue, using biophysical tools and theoretical approaches to link signaling to the forces involved.
3. Study the functional consequences of infection-induced mechanical imbalance on cell fate and host tissue integrity.

Significance of the Study

This study has a double interest: to better understand the impact of mechanics in the process of infection, for the development of new therapeutic strategies, and to bring new fundamental knowledge on the mechanical homeostasis of tissue barriers, by integrating extracellular pathogens as new tools to shed light on complex feedbacks between cell architecture, mechanics, and function.