Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence

Area of Science:

• Microbiology and Immunology
• Pathogen-Host Interactions
• Neuroscience

Background:

• Central nervous system infections are severe, with brain invasion mechanisms poorly understood.
• Listeria monocytogenes (Lm) causes neurolisteriosis, a deadly CNS infection, but bacterial neuroinvasion factors are unclear.
• While immunosuppression is a risk factor, bacterial contributions to neuroinvasion are largely unknown.

Purpose of the Study:

• To investigate bacterial factors contributing to Listeria monocytogenes neuroinvasion.
• To elucidate the mechanism by which Lm gains access to the central nervous system.
• To understand how Lm promotes its own persistence and transmission.

Main Methods:

• Development of a clinically relevant experimental model using hypervirulent Lm strains and a humanized mouse model.
• Investigation of the role of the bacterial surface protein InlB in host cell survival and immune evasion.
• Analysis of the molecular pathways involved, including c-Met, PI3 kinase, and FLIP, in response to InlB.

Main Results:

• The bacterial protein InlB protects infected monocytes from CD8+ T cell-mediated killing by inhibiting Fas-mediated cell death.
• This immune resistance mechanism, dependent on c-Met, PI3 kinase, and FLIP, increases infected monocyte lifespan.
• Prolonged monocyte survival facilitates Lm transfer to the brain and promotes Lm fecal shedding.

Conclusions:

• Listeria monocytogenes utilizes the surface protein InlB to confer cell-autonomous immune resistance, increasing host cell lifespan.
• This bacterial strategy promotes Lm persistence, dissemination to the central nervous system, and host-to-host transmission.
• InlB-mediated immune evasion is a critical virulence factor for Lm neuroinvasion and pathogenesis.