Biophysics of host/pathogen interaction during Neisseria meningitidis infection
Internship title: Biophysics of host/pathogen interaction during Neisseria meningitidis infection
Name: “Pathogenesis of Vascular Infections” Unit
Affiliation: Institut Pasteur, “Cell Biology and Infection” Department I
Address: 28 rue du Docteur Roux 75015 Paris
Name: Guillaume Duménil
Phone number: 0144389383
Name: Daria Bonazzi
Phone number: 0144389172
Subject Keywords: Biophysics, Neisseria meningitidis, host/pathogen interaction, mechanotransduction, membrane tension
Tools and methodologies: Live-cell Microscopy, immunofluorescence, micro-patterning, image analysis
Summary of lab’s interests: Neisseria meningitidis (Nm) is a pathogenic bacterium responsible for meningitis and sepsis in humans. During infection, bacteria adhere to the endothelium and proliferate inside blood vessels in the form of multicellular aggregates, leading to vascular colonization and damage. Upon adhesion, the bacterial colony induces plasma membrane (PM) remodeling of the host cell to resist the mechanical stress induced by the blood flow. All these processes rely on type IV pili (T4P), dynamic filamentous organelles protruding out of the bacterial body. The lab integrates a multidisciplinary approach combining microbiology with cell biology, vascular biology, chemistry and physics to study the pathogenesis of Nm infection.
Project summary: Upon bacterial adhesion, a complex cross-talk between Nm and endothelial cells is established, leading to the formation of filopodia-like membrane structures embedded in the growing bacterial aggregate. Following PM remodeling, several proteins get recruited underneath the microcolony, forming a honeycomb-like structure called ‘cortical plaque’. Even if some molecular mechanisms have been identified in the case of Nm infection, a global understanding of the colonization process is still missing. In particular, all these events highlight the potential role of mechanical forces at the bacteria/host cell interface for infection and disease progression.
In this project, we will focus on the physical forces and transduction mechanisms involved at different steps of this interaction, for instance:
1. forces bacteria can exert on the cell PM through passive adhesion or active T4P-mediated pulling;
2. forces generated by the cell PM, such as membrane tension and fluidity;
3. forces induced by the resulting reorganization of the actin cytoskeleton, which mediate the interaction between cells of the endothelium and cells with the underlying lamina.
These results will be part of a global project focusing on the mechanobiology of host/pathogen interaction between Nm and the human endothelium.
Interdisciplinary aspect of the project: To achieve this goal, the project integrates a multidisciplinary approach by combining classical cell biology techniques, live cell microscopy, microfabrication and image analysis. We propose to use micro-patterning to control the shape and polarity of the infected cell: this will allow a quantitative, systematic characterization of numerous parameters (e.g. bacterial positioning, host cell spreading area, cortical tension etc.) of the host cell reorganization upon bacterial adhesion and proliferation. Furthermore, we will use chemical and genetic perturbations of the system in combination with cell manipulation, for example using specific micro-patterns or substrates of different rigidities in order to fully understand their impact on the host cell response.