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Calcium signaling and microbial infections

Team leaders : Guy Tran Van Nhieu & Laurent Combettes

Summary of Research

Keywords : Cellular Microbiology - Invasion - Shigella - Cytoskeleton - Calcium Signalling - Type III secretion - Endoplasmic Reticulum Stress - Pneumococcus - Blood-Brain Barrier.

The team is studying the mechanisms of invasion by pathogenic bacteria. The main model studied is the enteroinvasive bacterium Shigella, the agent of bacillary dysentery, which invades colonic epithelial cells, replicates intracellularly and disseminates from cell to cell, inducing colonization and destruction. of the colonic mucosa. Specifically, we investigate the mechanisms of cytoskeleton diversion and the role of intracellular calcium signaling induced by bacterial effectors injected into the epithelial cell. The team is also studying calcium signaling associated with the mechanism of crossing the blood-brain barrier by pneumococcus, a commensal bacterium of the nasopharyngeal mucosa and major causative agent of bacterial meningitis. 

The team's work involves cellular systems of infections reconstituted in vitro, using different techniques of quantitative dynamic fluorescence microscopy (Ca2+imaging, TIRF, FRAP, FRET, etc.), integrated approaches of molecular and cellular biology, biochemistry and structural modeling. The team develops interdisciplinary projects involving national and international collaborations with mathematical modellers, biophysicists and membrane chemists.

Team composition

Guy Tran Van Nhieu, DR Inserm : team leader

Laurent Combettes, DR Inserm : team leader, head of the Inserm U1282

Sylvie Thietry, adjointe technique

Hamed Khakzad, post-doc

Benjamin Cocom-Chan, PhD student

Ilaria Pontisso, PhD student

Anu Susan Kurian, M1 student

Cellular and molecular diversion by Shigella type III effectors

A, Ca2+ microdomain at a Shigella invasion site induced by the type III secretion system. Top panels: Time-lapse pseudocolor images of cells loaded with the Ca2+ probe Fluo-4 infected by Shigella. Frame interval: 4 seconds. Arrow: Shigella invasion site. Bottom panels: Shigella invasion sites labeled for F-actin (red), inositol trisphosphate receptor type 1 (green) and Shigella LPS (Blue). Adapted from Sun CH et al., EMBO Journal, 2017.

B, Left: structural model of the D1D2 domains of the focal adhesion protein vinculin illustrating major conformational changes triggered by the Shigella type III effector IpaA. Right: rational design of cystein-clamped vinculin. Blue: D1 domain. Green: D2 domain in the closed conformer. Grey: D2 domain in the open conformer. Black: cystein clamp preventing the switch from closed to open conformer. Adapted from Valencia-Gallardo C, Aguilar D, Khakzad H, et al., BioRxive 2019.