Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques

• Type of Material: Article
• Authors: Maud Mavigner, Emory University; Jessica Raper, Emory University; Zsofia Kovacs-Balint, Emory University; Sanjeev Gumber, Emory University; Justin T. O'Neal, Emory Vaccine Center; Siddhartha Bhaumik, Emory University; Xiaodong Zhang, Emory University; Jakob Habib, Emory University; Cameron Mattingly, Emory University; Circe E. McDonald, Emory Vaccine Center; Victoria Avanzato, Emory University; Mark W. Burke, Howard University; Diogo M. Magnani, University of Miami; Varian K. Bailey, University of Miami; David I. Watkins, University of Miami; Thomas Vanderford, Emory University; Damien Fair, Oregon Health and Science University; Eric Earl, Oregon Health and Science University; Eric Feczko, Oregon Health and Science University; Martin Styner, University of North Carolina; Sherrie Jean, Emory University; Joyce Cohen, Emory University; Guido Silvestri, Emory University; R. Paul Johnson, Emory University; David H. O'Connor, University of Wisconsin; Jens Wrammert, Emory University; Mehul S. Suthar, Emory University; Mar Sanchez, Emory University; Maria Alvarado, Emory University; Ann Chahroudi, Emory University
• Language: English
• Date: 2018-04-04
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aao6975
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 10
• Issue: 435
• Start Page: eaao6975
• End Page: eaao6975
• Grant/Funding Information: This work was supported by the Pilot Grant Program of the YNPRC (P51 OD011132), the Emory Center for Childhood Infections and Vaccines, and Children’s Healthcare of Atlanta. Research reported in this publication was supported by the National Library of Medicine of the National Institutes of Health under Award Number T15LM007088 (to E. F.).
• Keywords: ADULT SOCIAL-BEHAVIOR; RECOGNITION MEMORY; ACUTE STRESSOR; NEONATAL HIPPOCAMPAL-LESIONS; Life Sciences & Biomedicine; Medicine, Research & Experimental; NEUROIMAGING FINDINGS; PREFRONTAL CORTEX; MACACA-MULATTA; CENTRAL-NERVOUS-SYSTEM; Cell Biology; RHESUS-MONKEYS; Research & Experimental Medicine; PICTORIAL ESSAY; Science & Technology
• Research Categories: Biophysics, Medical; Psychology, Behavioral; Biology, Cell

Abstract

No claim to original U.S. Government Works The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.