A nonhuman primate model mirrors human congenital cytomegalovirus infection and reveals a spectrum of vertical transmission outcomes

Manuel, T. D.; Mostrom, M. J.; Crooks, C.; Davalos, A.; Barfield, R.; Scheef, E. A.; Kendall, S.; Midkiff, C. C.; Sprehe, L. M.; Trexler, M.; Boquet, F.; Shroyer, M.; Danner, V.; Doyle-Meyers, L.; Mirza, A.; Lammi, S.; Otero, C. E.; Lee, M.; Rogers, L.; Kowalik, T.; Chan, C.; Permar, S. R.; Blair, R. V.; Frueh, K.; Malouli, D.; Granek, J. A.; Owzar, K.; Kaur, A.

doi:10.1101/2025.01.16.633406

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bioRxiv · 10.1101/2025.01.16.633406

A nonhuman primate model mirrors human congenital cytomegalovirus infection and reveals a spectrum of vertical transmission outcomes

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Abstract

Congenital cytomegalovirus (cCMV) is the leading infectious cause of birth defects worldwide, yet immune determinants of protection to inform design of a maternal vaccine remain elusive. Here, we characterized the outcome of primary rhesus CMV (RhCMV) infection during pregnancy in an immune competent nonhuman primate (NHP) model. RhCMV DNA was detected in amniotic fluid and/or fetal tissues in six of 12 (50% placental transmission) CMV-naive rhesus macaque dams inoculated intravenously with RhCMV in early second trimester gestation. Widespread tissue dissemination dominated by one of two inoculated RhCMV strains was present in one fetus (8.3% cCMV disease). Placental RhCMV transmission was associated with elevated fetal and maternal plasma TNF-alpha and reduced maternal brain-derived neurotrophic factor and IL-10 levels. CMV exposure during pregnancy had a broad impact on the placenta and fetus even in the absence of congenital infection as evidenced by RhCMV infection at the maternal-fetal interface in all 12 dams, along with significantly reduced placental efficiency and fetal growth metrics compared to gestation-matched control pregnancies. This NHP model recapitulates key aspects of human cCMV and provides new insight into barriers and biomarkers of successful vertical transmission. One sentence summary: The nonhuman primate model mirrors the epidemiology of human congenital CMV (cCMV) after primary infection and reveals its transmission bottlenecks.

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Manuel, T. D., Mostrom, M. J., Crooks, C., Davalos, A., Barfield, R., Scheef, E. A., Kendall, S., Midkiff, C. C., Sprehe, L. M., Trexler, M., Boquet, F., Shroyer, M., Danner, V., Doyle-Meyers, L., Mirza, A., Lammi, S., Otero, C. E., Lee, M., Rogers, L., Kowalik, T., Chan, C., Permar, S. R., Blair, R. V., Frueh, K., Malouli, D., Granek, J. A., Owzar, K., Kaur, A.. 2025-01-21. A nonhuman primate model mirrors human congenital cytomegalovirus infection and reveals a spectrum of vertical transmission outcomes. https://doi.org/10.1101/2025.01.16.633406

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