Efferocytosis, the process by which dying or dead cells are removed by phagocytosis, has an important role in development, tissue homeostasis and innate immunity1. 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 enzymes2. 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.
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We are grateful to S. Gray-Owen, S. Grinstein and D. Portnoy for providing reagents and advice and to D. Holmyard for help with electron microscopy. J.H.B. holds the Pitblado Chair in Cell Biology. Infrastructure for the Brumell laboratory was provided by a Leader’s Opportunity Fund grant from the Canadian Foundation for Innovation and the Ontario Innovation Trust. R.F. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research in partnership with the Canadian Association of Gastroenterology and the Crohn’s and Colitis Foundation of Canada. S.O. was supported by a postdoctoral fellowship from the Research Training Committee at the Hospital for Sick Children. This work was supported by an operating grant from The Arthritis Society of Canada (#RG11/013) to J.H.B. and a US Public Health Service grant (AI053669) from the National Institutes of Health to D.E.H.
Extended data figures
Cells were transfected with LifeAct-RFP (red) and then infected with wild type Lm expressing GFP at an MOI of 100 for 6h. Live infected cells were then analyzed by spinning disk confocal microscopy with Annexin V-Alexa 647 in the medium to label exofacial PS (blue). Frames from this video were cropped and are presented in Figure 3B. Images are representative of 3 independent experiments.
About this article
Nature Reviews Microbiology (2017)