Department of Medicine

Controlling the intracellular fate of cytosolic pathogens

A mosaic of septin cages

Project overview

Listeria monocytogenes, Shigella flexneri and Mycobacterium marinum are intracellular bacteria that have emerged independently as exceptional model organisms to address key issues in biology, including the ability of bacteria to move inside cells and be recognized by the immune system. Our group has recently discovered that the host cell employs septins, a novel component of the host cytoskeleton, to restrict the motility of S. flexneri and target them for destruction by autophagy, an important mechanism of innate immune defence. These results provide a new molecular framework to understand the emerging complexity of autophagy, and its ability to achieve specific clearance of intracytosolic bacteria. A major issue is now to fully decipher the underlying molecular and cellular events, and to validate these events analyzed in vitro during bacterial infection in vivo using relevant animal models. This information should provide vital clues towards understanding bacterial disease and for illuminating new therapeutic strategies.

Objectives

Using bacterial infection, we are currently focused on the following aims:

(1) To identify and characterize host and pathogen determinants underlying the intracellular fate of cytosolic bacteria

(2) To investigate the role of discovered molecules and mechanisms in vivo using zebrafish models of bacterial infection

It is expected that the completion of these objectives will provide insights into the mechanisms required for the control of infection by cytosolic host responses.

A variety of septin assemblies

Selected publications

Mostowy, S., and Cossart, P. (2012) Bacterial autophagy: restriction or promotion of bacterial replication? Trends Cell Biol. 22, 283-291.

Mostowy, S., and Cossart, P. (2012) Septins: the fourth component of the cytoskeleton. Nat. Rev. Mol. Cell Biol. 13, 183-194.

Mostowy, S., Bonazzi, M., Hamon, M., Mallet, A., Tham, T.N., Lelek, M., Gouin, E., Zimmer, C., Sartori, A., Kinoshita, M., Lecuit, M., and Cossart, P. (2010). Entrapment of intracytosolic bacteria by septin cage-like structures. Cell Host Microbe. 8, 433-444.

Funding

Wellcome Fellowship logo

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