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bioRxiv · 10.1101/2023.10.11.561759

Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection

Tisoncik-Go, J.·Stokes, C.·Whitmore, L.·Newhouse, D. J.·Voss, K.·Gustin, A.·Song, C.-J.·Smith, E.·Stencel-Baerenwald, J.·Parker, E. D.·Snyder, J. M.·Shaw, D.·Rajagopal, L.·Kapur, R. P.·Waldorf, K. A.·Gale, M.
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Abstract

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in non-microcephalic infants, of which the pathogenesis remains poorly understood. We utilized an established pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We found prenatal ZikV exposure led to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses revealed marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals showed multi-focal decompaction consistent with perturbation or remodeling of previously formed myelin, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/561759v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@c0d423org.highwire.dtl.DTLVardef@1a76f40org.highwire.dtl.DTLVardef@178e509org.highwire.dtl.DTLVardef@4d581_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Tisoncik-Go, J., Stokes, C., Whitmore, L., Newhouse, D. J., Voss, K., Gustin, A., Song, C.-J., Smith, E., Stencel-Baerenwald, J., Parker, E. D., Snyder, J. M., Shaw, D., Rajagopal, L., Kapur, R. P., Waldorf, K. A., Gale, M.. 2023-10-14. Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection. https://doi.org/10.1101/2023.10.11.561759

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