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

Abstract

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- and neuro-tropism 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 out 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 impacts neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.

Zika virus and the nonmicrocephalic fetus: why we should still worry

“…(48–50) A recent study in infant nonhuman primates also correlated ZIKV infection with hippocampal growth arrest, dysfunctional connectivity by functional MRI, and abnormal socioemotional processing. (51) Longitudinal studies are needed to understand the implications of ZIKV-associated injury to neurogenic cells in the fetus or young children and whether this injury might result in a predisposition to learning disorders, developmental delay or mental illness in childhood and adolescence.…”

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…The most severe consequences of infection are manifest in fetuses, which can develop devastating developmental aberrations, including microcephaly, collectively referred to as congenital Zika syndrome (Brasil et al, 2016; Del Campo et al, 2017). Infection of macaques, a natural host of ZIKV, during pregnancy frequently leads to fetal demise (Dudley et al, 2018), and in some non-human primate models, prenatal and early postnatal infection is associated with fetal and infant neuropathology and persistent functional and behavioral abnormalities (Coffey et al, 2018; Mavigner et al, 2018). …”

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

“…There have been conflicting reports on the neurologic complications and neurodevelopmental outcomes of children exposed to ZIKV in the peripartum and postnatal periods [26][27][28][29][30] . Studies with large numbers of cases have yet to be published, while research in animal models suggest that ZIKV infection during the postnatal period may also have a deleterious impact on development 31,32 . We recently demonstrated in infant rhesus macaques (RMs) that postnatal infection with ZIKV disseminates to the central and peripheral nervous systems with histologic features in the post-mortem brain similar to prenatal ZIKV infection 31 .…”

“…Studies with large numbers of cases have yet to be published, while research in animal models suggest that ZIKV infection during the postnatal period may also have a deleterious impact on development 31,32 . We recently demonstrated in infant rhesus macaques (RMs) that postnatal infection with ZIKV disseminates to the central and peripheral nervous systems with histologic features in the post-mortem brain similar to prenatal ZIKV infection 31 . Despite clearance of virus from blood after 7 days, brain structural and functional anomalies were detected up to 6 months after postnatal infection, including ventriculomegaly, blunted hippocampal growth, and weaker amygdala-hippocampus functional connectivity (FC) compared to uninfected infants.…”