Persistently primed microglia restrict the reactivation of latent cytomegalovirus at the expense of neuronal synaptic connectivity

Microglia are myeloid cells that reside within the central nervous system (CNS), where they maintain homeostasis under normal, non-pathological conditions. In addition, microglia also perform numerous immune functions upon different pathogenic stimuli, including CNS infections with various neurotropic viruses. Herpesviruses establish a lifelong latent infection from which they reactivate intermittently upon waning of immune control. The role of microglia in preventing reactivation of latent herpesviruses remains unclear. In this work, we used congenital cytomegalovirus (CMV) infection as a model to investigate the impact of a persistent virus infection of the brain on microglia. We show that mouse CMV (MCMV) latency in the CNS is associated with permanent microglial priming. The changes induced by persistent infection include continuous, interferon-gamma-dependent microglia activation and extensive transcriptional reprogramming at the single-cell level, leading to the expansion of a microglia subset associated with latent infection. Notably, the maintenance of microglia in a primed state provides enhanced control of latent infection and superior recall response but is associated with excessive loss of synaptic dendritic spines mediated by primed microglia. Altogether, our results indicate that latent CMV infection in the brain causes perturbation of microglial homeostasis, which leads to chronic neuroinflammation that successfully restricts virus reactivation but simultaneously compromises neuronal synaptic connectivity in the brain.