A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment

Abstract

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

ANKLE2‐related microcephaly: A variable microcephaly syndrome resembling Zika infection

“…While the CZS has gained much public attention, it is important to remember that congenital cytomegalovirus (cCMV) continues to be the most common congenital viral infection globally and is a common cause of neurodevelopmental disabilities, sensorineural hearing loss, and vision loss in children 38 . cCMV infection can also perturb developmental processes in the fetal and neonatal brain resulting in abnormalities that overlap many congenital MIC syndromes including cortical dysgenesis, intracranial (predominantly periventricular) calcifications, dysgenesis of the corpus callosum, cerebellar hypoplasia with additional features as well such as ventriculomegaly, lenticulostriate vasculopathy, periventricular cystic malformations, and fetal brain sequence disruption or arrest syndrome 39–41 . Of note, intracranial calcifications, as seen with cCMV, CZS, and other in utero infections, may be underreported in our series as most children underwent brain imaging by MR which has limited sensitivity for their detection.…”

Congenital cytomegalovirus infection and advances in murine models of neuropathogenesis

“…In the recent issue of JCI Insight ( Zhou et al., 2022 ), Zhou et al. established a novel mouse system to model cHCMV infection by intracranially (i.c.)…”

“…Furthermore, clinical manifestation of hearing loss can be variable and can include presentations such as delayed onset hearing loss, unilateral hearing loss, and progressive hearing loss post infection ( Moulden et al., 2021 ). Week 7–8 mice demonstrated significant hearing loss following infection with MCMV at E13.5 ( Zhou et al., 2022 ). This could have been in part due to the previously mentioned CMV-induced structural damage of the CNS.…”

“…In addition to these findings, varying degrees of degeneration have been observed in the cochlear vasculature following CMV infection ( Carraro et al., 2017 ). Treatment with ganciclovir was able to ameliorate the hearing loss ( Zhou et al., 2022 ; Haller et al., 2020 ), and protection was provided to prevent outer hair cell loss. These types of studies are vital as CMV-induced hearing loss is highly prevalent in children with symptomatic infection, and they are more likely to develop bilateral hearing loss ( Riga et al., 2018 ).…”

“…The most significant usefulness of the cMCMV system, in our opinion, is probably that it provides a tool for seeing how efficacious future therapeutics and vaccines may be at mitigating or preventing neurological complications in newborns ( Zhou et al., 2022 ). Ganciclovir is a nucleoside analogue and has been regularly administered to newborn babies diagnosed with cHCMV infection right after birth.…”