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

Jennifer Tisoncik-Go (), Caleb Stokes (), Leanne S. Whitmore, Daniel J. Newhouse, Kathleen Voss, Andrew Gustin, Cheng-Jung Sung, Elise Smith, Jennifer Stencel-Baerenwald, Edward Parker, Jessica M. Snyder, Dennis W. Shaw, Lakshmi Rajagopal, Raj P. Kapur, Kristina M. Adams Waldorf and Michael Gale ()
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Jennifer Tisoncik-Go: University of Washington
Caleb Stokes: University of Washington
Leanne S. Whitmore: University of Washington
Daniel J. Newhouse: University of Washington
Kathleen Voss: University of Washington
Andrew Gustin: University of Washington
Cheng-Jung Sung: University of Washington
Elise Smith: University of Washington
Jennifer Stencel-Baerenwald: University of Washington
Edward Parker: University of Washington
Jessica M. Snyder: University of Washington
Dennis W. Shaw: University of Washington
Lakshmi Rajagopal: University of Washington
Raj P. Kapur: University of Washington
Kristina M. Adams Waldorf: University of Washington
Michael Gale: University of Washington

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly understood. We utilize an established female pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We find prenatal ZikV exposure leads to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses reveal 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 shows multi-focal decompaction, 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.

Date: 2024
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DOI: 10.1038/s41467-024-49524-2

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