Prenatal exposure to the Zika virus (ZIKV) poses a threat to the fetus, putting the neonate at risk for significant birth defects (termed congenital Zika syndrome) and neurodevelopmental deficits developing during early child- hood. There are currently no predictors to indicate which children will develop deficits and the neuropathologies underlying these deficits is not defined. It is critical to predict which infants will later develop deficits to max- imize long-term sensorimotor development and functional outcomes. Furthermore, understanding underlying neuropathogenesis is necessary to develop targeted interventions. The purpose of this grant is to define the long-term neurodevelopmental outcomes of ZIKV by rapidly obtaining data from highly controlled studies of rhesus macaques. Specifically, we will:
Aim 1 : Characterize sensorimotor neurodevelopmental outcomes in macaques with prenatal ZIKV expo- sure. Behavioral assessments focused on sensorimotor development may highlight the distinct developmental trajectories and increased deficits with age in ZIKV-exposed rhesus macaques. Because macaques develop more quickly than humans, sensorimotor neurodevelopmental differences that occur by year 3 may predict future impacts in children born with prenatal ZIKV exposure.
Aim 2 : Identify early neural predictors of sensorimotor neurodevelopmental deficits in ZIKV-exposed infant macaques with quantitative MRI, hearing and visual studies. We will describe differences between ZIKV-exposed and mock-infection control infants and identify individual differences within ZIKV-exposed in- fants to determine the full spectrum of brain abnormalities.
Aim 3 : Define neuropathology underlying sensorimotor neurodevelopmental deficits with quantitative brain histopathology. Using cellular quantification and organization of brain nuclei, we aim to identify the neu- ropathogenesis of congenital Zika syndrome to better create appropriate, targeted interventions for children. This study utilizes a large cohort of ZIKV-exposed infant macaques that have been born in other NIH-funded studies and capitalizes on our collaborative team of experts in neuropathology, neurodevelopment and neu- roradiology.

Public Health Relevance

Pregnant women with Zika virus infection can transmit the virus to their unborn children, which results in mul- tiple birth defects including brain abnormalities, visual abnormalities, and hearing loss. It is important to define the full spectrum of symptoms, disease pathogenesis and early predictors of neurodevelopmental deficits in a controlled setting using a macaque model of Zika virus infection. This grant characterizes sensory and motor neurodevelopment in infant macaques and correlates these outcomes with brain abnormalities found on brain imaging and brain histopathology in order to identify early predictors of neurodevelopmental deficits that can be used to design future human clinical studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Morabito, Kaitlyn Melissa
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University of Wisconsin Madison
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