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Ocular and uteroplacental pathology in macaque congenital Zika virus infection

View ORCID ProfileEmma L. Mohr, Lindsey N. Block, Christina M. Newman, Laurel M. Stewart, Michelle Koenig, Matthew Semler, Meghan E. Breitbach, Leandro B.C. Teixeira, Xiankun Zeng, Andrea M. Weiler, Gabrielle L. Barry, Troy H. Thoong, Gregory J. Wiepz, Dawn M. Dudley, Heather A. Simmons, Andres Mejia, Terry K. Morgan, M. Shahriar Salamat, Sarah Kohn, Kathleen M. Antony, Matthew T. Aliota, Mariel S. Mohns, Jennifer M. Hayes, Nancy Schultz-Darken, Michele L. Schotzko, Eric Peterson, Saverio Capuano III, Jorge E. Osorio, Shelby L. O’Connor, Thomas C. Friedrich, David H. O’Connor, Thaddeus G. Golos
doi: https://doi.org/10.1101/195701
Emma L. Mohr
Department of Pediatrics, University of Wisconsin-Madison
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Lindsey N. Block
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Christina M. Newman
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Laurel M. Stewart
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Michelle Koenig
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Matthew Semler
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Meghan E. Breitbach
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Leandro B.C. Teixeira
Department of Pathobiological Sciences, University of Wisconsin-Madison
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Xiankun Zeng
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland
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Andrea M. Weiler
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Gabrielle L. Barry
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Troy H. Thoong
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Gregory J. Wiepz
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Dawn M. Dudley
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Heather A. Simmons
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Andres Mejia
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Terry K. Morgan
Departments of Pathology and Obstetrics & Gynecology, Oregon Health & Science University
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M. Shahriar Salamat
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Sarah Kohn
Department of Radiology, University of Wisconsin-Madison
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Kathleen M. Antony
Department of Obstetrics and Gynecology, University of Wisconsin-Madison
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Matthew T. Aliota
Department of Pathobiological Sciences, University of Wisconsin-Madison
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Mariel S. Mohns
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Jennifer M. Hayes
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Nancy Schultz-Darken
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Michele L. Schotzko
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Eric Peterson
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Saverio Capuano
Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Jorge E. Osorio
Department of Pathobiological Sciences, University of Wisconsin-Madison
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Shelby L. O’Connor
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
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Thomas C. Friedrich
Department of Pathobiological Sciences, University of Wisconsin-Madison Wisconsin National Primate Research Center, University of Wisconsin-Madison
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David H. O’Connor
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison Wisconsin National Primate Research Center, University of Wisconsin-Madison
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Thaddeus G. Golos
Wisconsin National Primate Research Center, University of Wisconsin-Madison Department of Obstetrics and Gynecology, University of Wisconsin-Madison Department of Comparative Biosciences, University of Wisconsin-Madison
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Abstract

Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM) and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout the fetus tissues and maternal immune system at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal lymph node, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in rhesus macaques. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital infection previously; further nonhuman primate studies are needed to determine if an increased risk for PPROM is associated with congenital Zika virus infection.

Author summary A ZIKV infection during pregnancy is associated with malformations in fetal development including, but not limited to, ocular and brain anomalies, such as microcephaly, and stillbirth. The development of an accurate pregnancy model to study the effects of ZIKV will provide insight into vertical transmission, ZIKV tissue distribution, and fetal injury and malformations. Non-human primates closely resemble human in terms of the reproductive system, immunity, placentation and pregnancy. Our study demonstrates that the rhesus macaque is a compelling model in which to study ZIKV during pregnancy due to similar outcomes between the human and rhesus macaque. These similarities include prolonged viremia, vertical transmission, adverse pregnancy outcomes and fetal pathology, including defects in the visual system.

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Posted September 30, 2017.
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Ocular and uteroplacental pathology in macaque congenital Zika virus infection
Emma L. Mohr, Lindsey N. Block, Christina M. Newman, Laurel M. Stewart, Michelle Koenig, Matthew Semler, Meghan E. Breitbach, Leandro B.C. Teixeira, Xiankun Zeng, Andrea M. Weiler, Gabrielle L. Barry, Troy H. Thoong, Gregory J. Wiepz, Dawn M. Dudley, Heather A. Simmons, Andres Mejia, Terry K. Morgan, M. Shahriar Salamat, Sarah Kohn, Kathleen M. Antony, Matthew T. Aliota, Mariel S. Mohns, Jennifer M. Hayes, Nancy Schultz-Darken, Michele L. Schotzko, Eric Peterson, Saverio Capuano III, Jorge E. Osorio, Shelby L. O’Connor, Thomas C. Friedrich, David H. O’Connor, Thaddeus G. Golos
bioRxiv 195701; doi: https://doi.org/10.1101/195701
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Ocular and uteroplacental pathology in macaque congenital Zika virus infection
Emma L. Mohr, Lindsey N. Block, Christina M. Newman, Laurel M. Stewart, Michelle Koenig, Matthew Semler, Meghan E. Breitbach, Leandro B.C. Teixeira, Xiankun Zeng, Andrea M. Weiler, Gabrielle L. Barry, Troy H. Thoong, Gregory J. Wiepz, Dawn M. Dudley, Heather A. Simmons, Andres Mejia, Terry K. Morgan, M. Shahriar Salamat, Sarah Kohn, Kathleen M. Antony, Matthew T. Aliota, Mariel S. Mohns, Jennifer M. Hayes, Nancy Schultz-Darken, Michele L. Schotzko, Eric Peterson, Saverio Capuano III, Jorge E. Osorio, Shelby L. O’Connor, Thomas C. Friedrich, David H. O’Connor, Thaddeus G. Golos
bioRxiv 195701; doi: https://doi.org/10.1101/195701

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