The impact of systemic bacterial and viral infections on innate immune responses in the brain. (360G-Wellcome-093268_Z_10_Z)

It is well known that systemic inflammation communicates with the brain but most of this research has been carried out using bacterial and viral mimetics. We will use real, transient bacterial and viral infections, in young and old mice, to model common infections of humans. We will study how these infections influence the phenotype of the innate immune cells in the brain, the macrophages and microglia, and also the endothelium. We will characterise the phenotypic changes and establish how long the changes last and whether different infectious agents produce similar or different phenotypes. We propose that the microglia become primed by a systemic infection such that they give an exaggerated response to a secondary stimulus. We will investigate the primed response by stimulating toll-like receptors and immunoregulatory receptors and studying the signalling pathways in microglia isolated from the brains of animals after a systemic infection. We will then confirm that the primed pheno type is present in vivo using inflammatory and neurotoxic stimuli. We propose that the microglia in the aged mouse brain will show an exaggerated priming response and that a secondary challenge will lead to heightened production of potentially neurotoxic molecules when compared to microglia from young animals.