No abstract

Human cytomegalovirus (HCMV) infection of the neonatal CNS results in long-term neurologic sequelae. To define the pathogenesis of fetal HCMV CNS infections, we investigated mechanisms of virus clearance from the CNS of neonatal Balb/c mice infected with murine CMV (MCMV). Virus titers peaked in the CNS between post-natal (PN) days 10–14 and infectious virus was undetectable by PN day 21. Congruent with virus clearance was the recruitment of CD8+ T-cells into the CNS. Depletion of CD8+ T cells resulted in death by postnatal day 15 in MCMV infected animals and increased viral loads in the liver, spleen and the CNS suggesting an important role for these cells in the control of MCMV replication in the newborn brain. Examination of brain mononuclear cells revealed that CD8+ T-cell infiltrates expressed high levels of CD69, CD44 and CD49d. IE1168 specific CD8+ T-cells accumulated in the CNS and produced IFN-γ and TNF-α but not IL-2 following peptide stimulation. Moreover, adoptive transfer of brain mononuclear cells resulted in decreased virus burden in immunodepleted MCMV infected syngeneic mice. Depletion of the CD8+ cell population following transfer eliminated control of virus replication. In summary, these results show that functionally mature virus specific CD8+ T-cells are recruited to the CNS in mice infected with MCMV as neonates.

Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice.

In children with symptomatic congenital CMV infection involving the CNS, viremia during early infancy is associated with hearing loss and systemic CMV disease.

Human cytomegalovirus (HCMV) is the most frequent cause of congenital viral infections in humans and