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.
Bibliographical noteFunding Information:
This work was supported by the Pilot Grant Program of the YNPRC (P51 OD011132), as well as funding from the Emory Center for Childhood Infections and Vaccines, and Children's Healthcare of Atlanta (all to A.C.). Research reported in this publication was supported by the National Library of Medicine of the NIH under award number T15LM007088 (to E.F.).
This study was conducted in strict accordance with U.S. Department of Agriculture regulations and the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, approved by the Emory University Institutional Animal Care and Use Committee (AWA# A3180-01), and conducted in an AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care)–accredited facility. Eight infant Indian RM (Macaca mulatta) including two males and six females were used in this study. The infants were delivered naturally by their dams while housed in indoor/outdoor social groups. Infants were then removed from their dams at 5 to 10 days of age and transported to the Yerkes National Primate Research Center (YNPRC) nursery facility. All infants were singly housed in warming incubators for the first 3 to 4 weeks. Infants were hand-fed formula every 2 to 3 hours for the first month, then via self-feeders for the next 3 months as per standard YNPRC protocol. Soft blankets, plush toys, or fleece were provided and changed daily. Soft chow and fruits were introduced starting at 1 month of age, and by 4 months, formula was discontinued and all were fed a diet of Purina Primate Chow, Old World Monkey formulation, supplemented with daily fruits and vegetables. Water was provided ad libitum. At 4 weeks of age, infants transitioned into age-appropriate caging with visual and auditory contact with conspecifics. At 6 to 7 weeks of age, they began socialization consisting of protected contact housing supplemented with 2 to 3 hours daily of full contact with their age-matched peer. By 3 months of age, each pair was housed entirely together. ZIKV-infected infants were housed in an ABSL-2+ (Animal Biosafety Level 2)
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