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Bacterial inhibition of CD8+ T-cells mediated cell death promotes neuroinvasion and within-host persistence [article]

Claire Maudet, Marouane Kheloufi, Sylvain Levallois, Julien Gaillard, Lei Huang, Charlotte Gaultier, Yu-Han Tsai, Olivier Disson, Marc Lecuit
2020 bioRxiv   pre-print
Central nervous system infections are amongst the most severe, yet 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 central nervous system infections. While immunosuppression is a well-established host risk factor for neurolisteriosis, little is known regarding the bacterial factors underlying Lm neuroinvasion. We have developed a
more » ... e developed a clinically-relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains inoculated in a humanized mouse model of infection, and we show that the bacterial protein InlB protects infected monocytes from CD8+ T-cells Fas-mediated cell death, in a c-Met/PI3-kinase/FLIP-dependent manner. This blockade of anti-Lm specific cellular immune response lengthens infected monocytes lifespan, favoring Lm transfer from infected monocytes to the brain. The intracellular niche created by InlB-mediated cell-autonomous immunosuppression also promotes Lm fecal shedding, accounting for its selection as a Lm core virulence gene. Here, we have uncovered an unanticipated specific mechanism by which a bacterial pathogen confers to the cells it infects an increased lifespan by rendering them resistant to cell-mediated immunity. This promotes Lm within-host persistence and dissemination to the central nervous system, and transmission.
doi:10.1101/2020.11.20.384974 fatcat:rf2znq36jjellbbh7gst54cdmq