Zika virus (ZIKV) infection can have devastating neurologic consequences for infants infected in utero, particularly during the first trimester. Little is known, however, about the impact of ZIKV infection close to the time of delivery or in the period of infancy.
To address this gap, we developed a model of postnatal ZIKV infection in infant rhesus macaques (RMs). Infant RMs were infected with 10(5) PFU of ZIKV strain PRVABC59 s.c. at five weeks of age. A subset of RMs was sacrificed soon after infection to determine tissue tropism of ZIKV in infants and another subset was followed longitudinally. Viral loads in plasma and tissues were measured by qPCR. Binding and neutralization antibody responses were quantified by ELISA and focus reduction neutralization test (FRNT), respectively. At three months of age, infant RMs underwent structural T1-weighted magnetic resonance imaging (MRI), resting-state functional MRI, and Diffusion Tensor Imaging (DTI). A Human Intruder task was used to quantify the response to acute stress.
Six infant RMs were challenged with ZIKV with peak viral loads in plasma at day 2-3 that cleared by day 7 after infection. ZIKV was not detected in urine, saliva, or CSF. Infant RMs developed anti-ZIKV binding IgG and IgM antibodies as well as neutralization activity in plasma. In two infant RMs sacrificed at the peak of viremia, ZIKV RNA was detected in multiple lymph nodes and the spleen. In two infant RMs sacrificed two weeks after infection, ZIKV RNA was additionally detected in the frontal cortex, parietal cortex, occipital cortex, cauda equina, and trigeminal ganglion. MRI and DTI performed at three months of age revealed increased size of the lateral ventricles, microstructural alteration in the corpus callosum, and reduction in the functional connectivity of the primary motor (M1) and somatosensory (S1) cortices in ZIKV-infected infant RMs as compared to age-matched controls. ZIKV-infected infants also showed emotional dysregulation, failing to demonstrate the species-typical freezing behavior in response to an acute social stressor as compared to similarly reared controls.
In summary, we demonstrate for the first time that postnatal ZIKV infection of infants disseminates into the central nervous system and has structural and functional neurologic consequences. This model can be used to test therapeutic approaches to prevent or reverse the damage caused by ZIKV infection in infants.