Persistent microglial activation following neonatal CMV infection mediates neurodegeneration.

Abstract

Human cytomegalovirus (HCMV) causes the most common congenital viral infection in the United States, with well-known acute and late-onset neurological pathologies. Moreover, HCMV, like multiple herpesviruses, has been associated with neuroinflammation and neurodegeneration. Using a well-established neonatal murine (M)CMV infection model, we found that early-life infection drove adult-onset neuron loss and neuropathology in the retina and brain, without evident viral reactivation. Pathology was associated with the persistence of highly activated and inflammatory damage-associated microglia. Transient depletion of these microglia before the development of pathology resulted in repopulation of the tissue by microglia with a more reparative profile, which was then sustained over time. Transient microglia depletion alone was sufficient to preserve retinal structure and photoreceptor neurons, promote healing of some existing retinal damage, and preserve brain neuron density in adult infected mice. Thus, early-life infection by MCMV promoted dysfunctional and pathogenic microglia that drove adult-onset neurodegeneration in the eye and brain.