Neurodevelopment after postnatal Zika virus infection in infant macaques

PROJECT SUMMARY / ABSTRACT Intense research has focused on the neurologic effects of prenatal Zika virus (ZIKV) infection; however, the consequences of postnatal infection early in life are understudied. Infants exposed to ZIKV in utero but born without microcephaly can develop postnatal microcephaly, neurologic dysfunction, and neurodevelopmental ab- normalities, highlighting the potential of ZIKV to cause ongoing damage after birth. This damage is likely related to the exponential maturation of the brain that occurs during the first 2 years of life, particularly in temporal, prefrontal and parietal regions important for emotional, social and executive functions, including learning, atten- tion and memory. Our group has previously reported that postnatal ZIKV infection causes abnormalities in brain structure, function, and behavior in a pilot study of infant rhesus macaques (RMs) infected postnatally. Here, we propose to extend the scope and duration our prior pilot study and generate novel data regarding the impact of postnatal ZIKV infection on the developing brain. The Objective of this application is to bring new mechanistic insights into postnatal ZIKV infection to address the existing knowledge gap regarding outcomes and host-virus interactions. We will use our postnatal ZIKV-RM model to interrogate the neurobehavioral impact of ZIKV infection at different stages of postnatal brain develop- ment, with approaches that span from single cells to whole animal. This model of postnatal ZIKV exposure allows us to generate key data on the mechanisms by which ZIKV and/or the immune response to infection leads to cellular changes that ultimately result in aberrant postnatal development of limbic structures and behavioral def- icits later in life. We hypothesize that 1) ZIKV and/or the immune response to infection disproportionately affects limbic structures in the postnatally developing brain; 2) cellular changes in these limbic structures lead to aberrant neurodevelopment and abnormal behaviors; and 3) there may be a period of vulnerability to ZIKV during post- natal brain development. We will test our hypotheses in these Specific Aims: 1) Determine the spectrum of abnormal behavior and cognition following ZIKV infection of infant RMs at different stages of brain development; 2) Identify developmental trajectories of brain structure and function following postnatal ZIKV infection of infant RMs at different stages of brain development; and 3) Define the neurodevelopmental pathways and cell types impacted by postnatal ZIKV infection. This work will include RM infants infected with ZIKV at 1 or 6 months of age (equivalent to 4 and 24 month old humans) as well as age- and rearing-matched and viral mimic controls, that over their first 2 years of life will undergo a series of detailed assessments including validated tests of soci- oemotional behavior and cognition, structural and functional brain imaging, brain histology, stereology and single cell and bulk cell transcriptomics. Our results may have important public health implications for children living in ZIKV-endemic/epidemic areas as well as for travelers to these regions.