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Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence

Abstract : Infections of the central nervous system are among the most serious infections1,2, but the mechanisms by which pathogens access the brain remain poorly understood. The model microorganism Listeria monocytogenes (Lm) is a major foodborne pathogen that causes neurolisteriosis, one of the deadliest infections of the central nervous system3,4. Although immunosuppression is a well-established host risk factor for neurolisteriosis3,5, little is known about the bacterial factors that underlie the neuroinvasion of Lm. Here we develop a clinically relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains6 inoculated in a humanized mouse model of infection7, and we show that the bacterial surface protein InlB protects infected monocytes from Fas-mediated cell death by CD8+ T cells in a manner that depends on c-Met, PI3 kinase and FLIP. This blockade of specific anti-Lm cellular immune killing lengthens the lifespan of infected monocytes, and thereby favours the transfer of Lm from infected monocytes to the brain. The intracellular niche that is created by InlB-mediated cell-autonomous immune resistance also promotes Lm faecal shedding, which accounts for the selection of InlB as a core virulence gene of Lm. We have uncovered a specific mechanism by which a bacterial pathogen confers an increased lifespan to the cells it infects by rendering them resistant to cell-mediated immunity. This promotes the persistence of Lm within the host, its dissemination to the central nervous system and its transmission.
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Submitted on : Thursday, July 7, 2022 - 1:57:02 PM
Last modification on : Friday, August 5, 2022 - 12:03:01 PM

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Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License

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Claire Maudet, Marouane Kheloufi, Sylvain Levallois, Julien Gaillard, Lei Huang, et al.. Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence. Nature, Nature Publishing Group, 2022, 603 (7903), pp.900-906. ⟨10.1038/s41586-022-04505-7⟩. ⟨pasteur-03716395⟩

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