Neural route of cerebral Listeria monocytogenes murine infection: Role of immune response mechanisms in controling bacterial neuroinvasion

The pathologic features of cerebral Listeria monocytogenes infection strong ly suggest that besides hematogenous spread, bacteria might also spread via a neural route. We propose that after snout infection of recombination act ivating gene 1 (RAG-1)-deficient mice, L, monocytogenes spreads to the brai n via a neural route. The neural route of invasion is suggested by (i) the immunostaining of L, monocytogenes in the trigeminal ganglia (TG) and brain stem but not in other areas of the brain; (ii) the kinetics of bacterial l oads in snout, TG, and brain; and (iii) the increased resistance of mice in fected with a plcB bacterial mutant (unable to spread from cell to cell). G amma interferon (IFN-gamma) plays a protective role in neuroinvasion; induc ible nitric oxide synthase (iNOS) accounts only partially for the protectio n, as shown by a comparison of the susceptibilities of IFN-gamma receptor ( IFN-gammaR)-deficient, iNOS-deficient, and wild-type mice to snout infectio n with L, monocytogenes. The dramatically enhanced susceptibility of RAG-1- deficient, IFN-gammaR gene-deficient mice indicated the overall importance of innate immune cells in the release of protective levels of IFN-gamma, Th e source of IFN-gamma appeared to be NK cells, as shown by use of RAG-1-def icient, gamma -chain receptor gene-deficient mice; NK cells played a releva nt protective role in neuroinvasion through a perforin-independent mechanis m. In vitro evidence indicated that IFN-gamma can directly induce bacterios tatic mechanisms in neural tissue.