Abstract
Background
Cytomegalovirus (CMV) is a leading infectious cause of neurologic deficits, both in the settings of congenital and perinatal infection, but few animal models exist to study neurodevelopmental outcomes. This study examined the impact of neonatal guinea pig CMV (GPCMV) infection on spatial learning and memory in a Morris water maze (MWM) model.
Methods
Newborn pups were challenged intraperitoneally (i.p.) with a pathogenic red fluorescent protein-tagged GPCMV, or sham inoculated. On days 15–19 post infection (p.i.), pups were tested in the MWM. Viral loads were measured in blood and tissue by quantitative PCR (qPCR), and brain samples collected at necropsy were examined by histology and immunohistochemistry.
Results
Viremia (DNAemia) was detected at day 3 p.i. in 7/8 challenged animals. End-organ dissemination was observed, by qPCR, in the lung, liver, and spleen. CD4-positive (CD4+) and CD8-positive (CD8+) T cell infiltrates were present in brains of challenged animals, particularly in periventricular and hippocampal regions. Reactive gliosis and microglial nodules were observed. Statistically significant spatial learning and memory deficits were observed by MWM, particularly for total maze distance traveled (p < 0.0001).
Conclusion
Neonatal GPCMV infection in guinea pigs results in cognitive defects demonstrable by the MWM. This neonatal guinea pig challenge model can be exploited for studying antiviral interventions.
Impact
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CMV impairs neonatal neurocognition and memory in the setting of postnatal infection.
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The MWM can be used to examine memory and learning in a guinea pig model of neonatal CMV infection.
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CD4+ and CD8+ T cells infiltrate the brain following neonatal CMV challenge.
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This article demonstrates that the MWM can be used to evaluate memory and learning after neonatal GPCMV challenge.
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The guinea pig can be used to examine central nervous system pathology caused by neonatal CMV infection and this attribute may facilitate the study of vaccines and antivirals.
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Acknowledgements
We would like to thank Dr. Thomas Pengo, for his assistance with the use of the Imaris software and Steve Ricchio, who helped us to obtain the confocal images. This work was supported by NIH HD079918, HD098866, and NS038836.
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Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: C.F.-A., L.E.M., M.A.M., J.R.L., S.H., M.A.B., K.M.A., B.C.J., and M.R.S. Drafting the article or revising it critically for important intellectual content: C.F.-A., L.E.M., M.A.M., J.R.L., S.H., M.A.B., K.M.A., and M.R.S. Final approval of the version to be published: C.F.-A., L.E.M., M.A.M., J.R.L., S.H., M.A.B., K.M.A., B.C.J., and M.R.S.
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Fernández-Alarcón, C., Meyer, L.E., McVoy, M.A. et al. Impairment in neurocognitive function following experimental neonatal guinea pig cytomegalovirus infection. Pediatr Res 89, 838–845 (2021). https://doi.org/10.1038/s41390-020-1010-7
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DOI: https://doi.org/10.1038/s41390-020-1010-7
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