Cytomegalovirus has been intertwined with postnatal immune development in a host-specific fashion for
millions of years. CMV infects most children worldwide in the first year without acute complications. In
contrast, CMV causes overt encephalitis in selected small infants and in immuno-suppressed patients. We
have found that mouse CMV (mCMV) transiently reprograms fully differentiated macrophages with respect
to their immunophenotype, transcriptome and proteome, leading to the acquisition of stem cell-like
properties and a unique ameboid migratory behavior. Furthermore, mCMV infected macrophages provide
their cell cycle machinery to viral proliferation. The Wnt pathway is critical in mCMV-induced
reprogramming. The complex transformation process allows for viral spread while minimizing clinical
pathology in a mouse model of mCMV lung infection.
In CMV encephalitis the virus spreads from periventricular regions and CNS interfaces, which are inhabited
by distinct CNS macrophage subsets, to other regions of the brain. Here, we will explore neonatal and adult
models of mCMV encephalitis to interlink autonomous reprogramming of CNS macrophage subsets with
antiviral activity, immunopathology and neurological damage. Thus, we will characterize the diversity of
CNS macrophages involved in mCMV encephalitis. Particular foci will be the Wnt pathway and long-term
macrophage development, including epigenetic imprinting and the response to subsequent infections.