A surface-exposed region of the UL37 protein that is essential for alphaherpesvirus neuroinvasion

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 DESCRIPTION (provided by applicant): Alphaherpesviruses are pathogens that proficiently invade the nervous system of an immunocompetent host. Spread of these neuroinvasive herpesviruses from sensory neurons to the eye, brain or from mother to newborn, are significant causes of morbidity and mortality. Herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) are representative members of the two genuses of mammalian neuroinvasive herpesviruses (simplexviruses & varicelloviruses). These viruses rely on spread to the nervous system to establish life-long latent infections, yet very little is known regarding the molecular mechanisms that underlie this remarkable trait. The UL37 protein is a conserved structural component of the alphaherpesvirus virion. Our lab recently identified three highly conserved surface-exposed regions in the amino terminal half of this protein. As part of my preliminary data for this proposal I demonstrated that pseudorabies virus (PRV) mutated in one of these regions, designated R2, replicates to near wild-type titers in epithelial cells, however fails to invade the host nervous system due to a defect in sustained retrograde transport within the axon. This proposal is founded on the hypothesis that UL37 performs critical effector functions that are required during neural delivery. The experiments proposed will examine the mechanism by which this mutant is defective at long distance axon transport as well as determine if the effector functions of the R2 region are conserved in the human pathogen, HSV-1. The R2 mutant has the capacity to generate a robust immune response due to its replication in peripheral cells. This property in combination with the loss in neuroinvasive capabilities makes the R2 mutant uniquely suited to advance the development of live-attenuated vaccines against both human and veterinary alphaherpesvirus infection by preventing latency establishment.