NK cells mediate neuroinflammation and brain pathology following congenital MCMV infection

Human cytomegalovirus (HCMV) is the major viral cause of congenital infection with severe developmental and functional sequelae. Even infants with asymptomatic congenital HCMV infection can present long-term central nervous system (CNS) manifestations. Since HCMV is strictly species-specific, studies of the pathogenesis of congenital cytomegalovirus (cCMV) infection rely on animal models. Infection of newborn mice with mouse cytomegalovirus (MCMV) recapitulates the hallmarks of congenital HCMV infection including brain inflammation and microglia activation as well as altered cerebellar development. We have shown previously that mitigation of inflammation prevented these developmental defects, indicating that the host inflammatory factors are key drivers of altered cerebellar development. Herein, we found not only that viral replication in brain is required for activation of microglia, but also that microglial transcriptome is dramatically altered in response to MCMV infection. Moreover, we have shown that microglia-derived chemokines recruit natural killer (NK) cells into the infected brain in CXCR3-dependent manner. Interferon gamma (IFN-?) released by highly activated brain infiltrating NK cells acts by activating Sonic hedgehog (SHH) pathway followed by expression of genes critical for granule neuron precursor cells (GNPC) proliferation, which ultimately results in increased thickness of external granular layer (EGL). Importantly, NK cells, although fail to control virus infection in the brain, orchestrated early local inflammatory responses which lead to altered cerebellar development.