Salmonella Infection in The Murine Brain

This project was initiated one year ago. The purpose of the study is to investigate bacterial meningitis using a mouse model of infection with Salmonella Typhimurium. We are using C57/BL6 mice that are genetically susceptible to infection with Salmonella Typhimurium due to an inactivating mutation in the natural resistance-associated macrophage protein 1 (NRAMP1). Nramp1 exerts many pleiotropic effects on macrophage functions and plays an important role in the control of several intracellular bacterial pathogens including Salmonella Typhimurium. The genetically susceptible Nramp1-/- mice are being compared to Nramp+/+ reconstituted C57BL6 mice that develop a more controlled sustained infection over several weeks. Following oral administration of Salmonella Typhimurium, we could recover viable Salmonella from the brains of both Nramp1-/- and Nramp1+/+ mice within 3-6 days. In Nramp1-/- mice there was a tight correlation between the levels of viable bacteria in the blood and those in the brain, although somewhat surprisingly bacteria were recovered from the brain even in animals with very low levels of bacteremia. In Nramp1+/+ mice there was no correlation between the levels in the blood and dissemination in the brain. In both models the majority of animals showed no clinical signs of CNS infections but histopathology revealed patchy meningitis in the brains of many of the infected animals. A small number of Nramp1+/+ mice developed severe ataxia and these mice had very high bacterial burdens in the brain (2-3 logs higher than in any others) and histological signs of severe meningioencephalitis, vasculitis and abscesses, all of which are characteristic of Salmonella meningitis in humans. Flow cytometric analysis of brains from infected asymptomatic animals revealed a correlation between bacterial burden and infiltration of macrophages/monocytes in the brain.