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.
Highlights
Congenital cytomegalovirus infection is the leading infectious cause of birth defects, primarily expressed as neurodevelopmental disorders [1]
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 Congenital cytomegalovirus (cCMV) infection
To more accurately represent early–first trimester cCMV infection, which is highly associated with severe neurological outcomes [20], a congenital murine CMV (cMCMV) infection mouse model was established by i.c. injection of recombinant murine cytomegalovirus (MCMV) (K181-eGFP strain) into the lateral ventricles of fetuses to initiate CMV infection in fetal brain at E13.5 (Figure 1A) [21]
Summary
Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of birth defects, primarily expressed as neurodevelopmental disorders [1]. Between 5% and 10% of infected infants show symptoms at birth, manifested by hepatosplenomegaly, jaundice, petechial rash, brain calcification, or microcephaly. 10% to 15% of asymptomatic infected infants subsequently develop late-onset sequelae during infancy or childhood, including sensorineural hearing loss (SNHL), intellectual disability, autism, and epilepsy [2]. The association with CMV infection was identified in 1956 [3], but the neuropathogenic mechanisms that result in abnormal fetal brain development and long-term neurodevelopmental disorders remain poorly characterized. A major obstacle for addressing these important questions has been the lack of suitable animal models of cCMV infection to study long-term brain damage and associated neurodevelopmental disorders [4]
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