Bacterial inhibition ofFas-mediated killing promotes neuroinvasion and persistence

Infections of the central nervous system are among the most serious infections(1,2), 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 system(3,4). Although immunosuppression is a well-established host risk factor for neurolisteriosis(3)(,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 strains(6) inoculated in a humanized mouse model of infection(7), and we show that the bacterial surface protein InIB protects infected monocytes from Fas-mediated cell death by CD8(+) T cells in a manner that depends on c-Met, P13 kinase and FLIP. This blockade of specific anti-Lm cellular immune killing lengthensthe lifespan of infected monocytes, and thereby favours the transfer of Lm from infected monocytes to the brain. The intracellular niche that is created by InIB-mediated cell-autonomous immune resistance also promotes Lm faecal shedding, which accounts for the selection of InIB 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.