Project Summary/ Abstract Congenital and perinatal infections are a leading cause of fetal and infant morbidity and mortality. There is increasing evidence that brain injury in babies with congenital and perinatal infections is caused not only by direct injury from the pathogen itself, but also may be due to the inflammatory or immune response to the pathogen. Targeted immunotherapies that allow pathogen control and removal but minimize bystander brain injury are largely unexplored. This proposal investigates the role of the receptor tyrosine kinase, Mertk, in cognitive and behavioral dysfunction in mice after congenital Zika virus (ZIKV) infection. Recent global epidemics link congenital ZIKV infection to neurodevelopmental abnormalities including microcephaly, intracranial calcifications, ventriculomegaly, and cognitive and behavioral impairment. Recent data indicate that ZIKV- exposed children without major structural brain abnormalities at birth may still have cognitive and behavioral deficits. Mertk, a receptor tyrosine kinase expressed by astrocytes and microglia, has been implicated in autoimmune, infectious and oncologic processes. It is not expressed by neurons, so immune-specific pathways can be probed without disturbing neuronal biology. Mertk facilitates microglial- and astrocyte- mediated synaptic pruning during early brain development and also mediates phagocytosis of cells and cellular debris in the brain. The hypotheses to be tested are: (1) Increased prenatal and early postnatal Mertk signaling during congenital ZIKV infection mediates immune-mediated neuronal injury; (2) increased postnatal Mertk signaling in microglia and astrocytes during congenital ZIKV leads to increased phagocytosis of mature neurons and synaptic pruning; and (3) increased Mertk signaling due to congenital ZIKV infection mediates abnormalities in functional connectivity, cognition, and behavioral deficits following congenital ZIKV infection. Understanding mechanisms of brain injury in ZIKV-exposed children is critical for providing interventions that improve neurodevelopment once ZIKV is detected. The proposed mechanisms also have broader implications for the effects of other neuroinflammatory insults on the developing brain. This mentored career development award provides the applicant, a uniquely trained pediatric neurologist with expertise in medical image analysis, formal training in animal models of early neurodevelopment along with advanced neuroimmunology and developmental neuroscience research methods, including immune cell profiling, histochemical analysis of brain tissue and optical imaging of functional brain cortical connectivity. The environment for the proposed research is an institution that is deeply committed to development of early career physician scientists and provides the applicant direct access to field leaders in developmental neuroscience, infectious diseases and widefield optical imaging. The training and data that will result from this award will provide a foundation for the applicant to transition to an independent physician scientist and lead critical, rigorous studies in the development of mouse models of congenital and perinatal infections that affect the developing brain.

Project Narrative Recent global outbreaks have linked congenital Zika virus (ZIKV) infection to significant problems with brain function in affected infants. This study will define the role of the protein, MERTK, in brain injury and neurodevelopmental abnormalities associated with congenital ZIKV. Understanding the mechanisms of brain injury in ZIKV-exposed children is critical for developing interventions that improve neurodevelopment in ZIKV- infected children and has implications for our understanding of other infant brain injuries associated with neuroinflammation.