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.
Alphaherpesvirus are the leading cause of sporadic fatal encephalitis worldwide and blindness in industrialized countries. These viruses exhibit dual tropism, replicating in epithelial cells prior to transmission into neurons. We have identified a highly conserved region of a structural component of pseudorabies virus (PRV; a member of the varicellovirus neuroinvasive genus) that plays a vital role in infection of neurons. I propose to investigate the mechanism by which this region promotes infection in neurons, and determine if this function in conserved in the human neuroinvasive alphaherpesvirus, herpes simplex virus (HSV-1).
| Richards, Alexsia L; Sollars, Patricia J; Smith, Gregory A (2016) New tools to convert bacterial artificial chromosomes to a self-excising design and their application to a herpes simplex virus type 1 infectious clone. BMC Biotechnol 16:64 |
