Cytomegalovirus (CMV) remains the most common congenital infection and leading cause of birth defects in children in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. However, the mechanisms of injury and immune protection in the brain during CMV infections are currently not known. Previous work has demonstrated that CD8+ T cells play an integral role in the clearance of CMV in the brain, but how these cells are recruited and maintained remains poorly understood. To fill this critical gap in our knowledge, we employed a mouse model of congenital CMV and performed a detailed analysis of CMV-specific CD8+ T cell homing to the brain. Surprisingly, the preliminary data suggests, for the first time, that the CMV-infected brain may be using similar mechanisms of CD8+ T cell homing as the small intestine. In the gut, retinoic acid induces the expression of the chemokine receptor CCR9 on lymphocytes, which binds to the CCL25 chemokine produced by intestinal epithelial cells. Similarly, we found that CCR9 was preferentially upregulated on CD8+ T cells trafficking to the brain after persistent CMV infection, and both retinoic acid and CCL25 were expressed in the choroid plexus. Based on this data, we hypothesize that interactions of CCR9 and CCL25 regulate the inflammatory immune response in the brain after congenital CMV infection. To test our hypothesis, we will first use CCR9 KO mice to determine whether CD8+ T cells exhibit any defects in migration, survival, or immune protection in the brain during infection. Then, we will use mice that express a dominant negative retinoic acid receptor (dnRAR) in lymphocytes to determine whether retinoic acid is involved in regulating expression of CCR9 and homing of CD8+ T cells to the MCMV-infected brain. Knowledge gained from these studies will provide the necessary framework for developing novel diagnostics and therapeutics for the treatment of congenital CMV disease.
Cytomegalovirus is the leading cause of birth defects in the United States. Upon completion of this proposal, we expect to have a better mechanistic understanding of the host response to infection, allowing us to develop strategies to enhance immunity in early life.
