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Paper Chase

Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread.

Nature. May 8, 2014;509(7499):230-4.
Czuczman MA, Fattouh R, van Rijn JM, Canadien V, Osborne S, Muise AM, Kuchroo VK, Higgins DE, Brumell JH.

1] Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S1A8, Canada [3] Institute of Medical Science, University of Toronto, Toronto, Ontario M5S1A8, Canada [4] Sickkids IBD Centre, Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada.

Abstract:

Efferocytosis, the process by which dying or dead cells are removed by phagocytosis, has an important role in development, tissue homeostasis and innate immunity. Efferocytosis is mediated, in part, by receptors that bind to exofacial phosphatidylserine (PS) on cells or cellular debris after loss of plasma membrane asymmetry. Here we show that a bacterial pathogen, Listeria monocytogenes, can exploit efferocytosis to promote cell-to-cell spread during infection. These bacteria can escape the phagosome in host cells by using the pore-forming toxin listeriolysin O (LLO) and two phospholipase C enzymes. Expression of the cell surface protein ActA allows L. monocytogenes to activate host actin regulatory factors and undergo actin-based motility in the cytosol, eventually leading to formation of actin-rich protrusions at the cell surface. Here we show that protrusion formation is associated with plasma membrane damage due to LLO's pore-forming activity. LLO also promotes the release of bacteria-containing protrusions from the host cell, generating membrane-derived vesicles with exofacial PS. The PS-binding receptor TIM-4 (encoded by the Timd4 gene) contributes to efficient cell-to-cell spread by L. monocytogenes in macrophages in vitro and growth of these bacteria is impaired in Timd4(-/-) mice. Thus, L. monocytogenes promotes its dissemination in a host by exploiting efferocytosis. Our results indicate that PS-targeted therapeutics may be useful in the fight against infections by L. monocytogenes and other bacteria that use similar strategies of cell-to-cell spread during infection.