Two Modes of Pseudorabies Virus Neuroinvasion and Lethality in Mice

Abstract

We describe two distinct modes of neuroinvasion and lethality after murine flank inoculation with virulent and attenuated strains of pseudorabies virus (PRV). Mice infected with virulent (e.g., PRV-Becker, PRVKaplan, or PRV-NIA3) strains self-mutilate their flank skin in response to virally induced pruritus, die rapidly with no identifiable symptoms of central nervous system (CNS) infection such as behavioral abnormalities, and have little infectious virus or viral antigen in the brain. In distinct contrast, animals infected with an attenuated PRV vaccine strain (PRV-Bartha) survive approximately three times longer than wild-type PRVinfected animals, exhibit severe CNS abnormalities, and have an abundance of infectious virus in the brain at the time of death. Interestingly, these animals have no skin lesions and do not appear pruritic at any time during infection. The severe pruritus and relatively earlier time until death induced by wild-type PRV infection may reflect the peripheral nervous system (PNS) and immune responses to infection rather than a fatal, virally induced CNS pathology. Based on previously characterized afferent (sensory) and efferent (motor) neuronal pathways that innervate the skin, we deduced that wild-type virulent strains transit through the PNS via both afferent and efferent routes, whereas PRV-Bartha travels by only efferent routes in the PNS en route to the brain.Pseudorabies virus (PRV), a swine alphaherpesvirus, is a member of the alphaherpesvirus subfamily, including human and animal pathogens such as varicella-zoster virus, herpes simplex virus type 1 (HSV-1) and HSV-2, bovine herpesvirus types 1 and 5, and equine herpesviruses types 1 and 4 (23). Although the natural hosts of PRV are adult swine, PRV is pantropic, infecting avian embryos and a wide range of mammalian species, with the notable exceptions of humans and other higher-order species of nonhuman primates.PRV routinely establishes a latent infection in PNS ganglia of adult swine and yet rarely invades the central nervous systems (CNS) of these animals (8). Viral spread between adult swine occurs primarily via direct mucosal contact. Common sequelae of wild-type PRV infection include respiratory disease, weight loss, and infertility in pregnant gilts and sows (31). In contrast, PRV infection is lethal in neonatal piglets and in nonnative hosts such as cows, dogs, rodents, and other susceptible animals. In these animals, infection induces severe, uncontrollable pruritus (itchiness), culminating in frantic selfmutilating behavior historically described as "mad itch." Death ensues within days of infection with virulent strains of PRV. The cause of death of these animals has traditionally been ascribed to fatal encephalitis.Adult swine infected with live, attenuated vaccine strains such as PRV-Bartha typically exhibit few, if any, symptoms of infection. In addition, most attenuated PRV strains are significantly less virulent in nonnative hosts such as rodents (8). Despite the attenuated phenotype, PRV-Bartha remains neuroinvas...

Herpes Simplex Virus Type 1 Glycoprotein E Mediates Retrograde Spread from Epithelial Cells to Neurites

“…The accessibility of free neurites at certain anatomic sites may explain the variation in retrograde spread defects observed with different animal models after infection with gE-deleted HSV-1. Interestingly, gE-deleted PRV and bovine herpesvirus 1 (BHV-1) retain retrograde spread activity in animals, although these viruses produce small plaques in culture (3,8,11,31,35,46,51,(53)(54)(55). These findings may indicate that PRV and BHV-1 rely less on gE for epithelial cell-to-neuron spread than does HSV-1.…”

“…In this model, gE-deleted HSV-1 replicates in the skin but is not detected in the DRG (9,44). This phenotype differs from gE-deleted PRV, which is able to reach the DRG at WT levels (8). Thus, unlike PRV, gE-deleted HSV-1 viruses have a retrograde spread defect in vivo.…”

“…Three PRV proteins, glycoprotein E (gE), gI, and Us9, have been shown to mediate anterograde neuronal spread both in animal models of infection and in cultured neurons. However, these three proteins are dispensable for retrograde spread (3,8,11,12,31,46). In contrast, numerous animal models of infection have shown that HSV-1 gE is required for retrograde spread from the inoculation site to the cell bodies of innervating neurons (4,9,44,56).…”

Molecular Biology of Pseudorabies Virus: Impact on Neurovirology and Veterinary Medicine

“…To study a primary PRV infection of an epithelial surface, Brittle et al adapted a skin infection model well known in the HSV pathogenesis literature (51,368,426). In this model, shaved mouse skin flank is scarified and infected with a drop of viral inoculum, such that viral adsorption occurs on the underlying live epithelial tissue.…”

“…These include the chicken embryo eye model (18), the rat eye model of infection (45,222), the mouse skin flank model (51), and the mouse nasopharyngeal infection model (14).…”