The Neuropathic Itch Caused by Pseudorabies Virus

Abstract

Pseudorabies virus (PRV) is an alphaherpesvirus related to varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1). PRV is the causative agent of Aujeskzy's disease in swine. PRV infects mucosal epithelium and the peripheral nervous system (PNS) of its host where it can establish a quiescent, latent infection. While the natural host of PRV is the swine, a broad spectrum of mammals, including rodents, cats, dogs, and cattle can be infected. Since the nineteenth century, PRV infection is known to cause a severe acute neuropathy, the so called "mad itch" in non-natural hosts, but surprisingly not in swine. In the past, most scientific efforts have been directed to eradicating PRV from pig farms by the use of effective marker vaccines, but little attention has been given to the processes leading to the mad itch. The main objective of this review is to provide state-of-the-art information on the mechanisms governing PRV-induced neuropathic itch in non-natural hosts. We highlight similarities and key differences in the pathogenesis of PRV infections between non-natural hosts and pigs that might explain their distinctive clinical outcomes. Current knowledge on the neurobiology and possible explanations for the unstoppable itch experienced by PRV-infected animals is also reviewed. We summarize recent findings concerning PRV-induced neuroinflammatory responses in mice and address the relevance of this animal model to study other alphaherpesvirus-induced neuropathies, such as those observed for VZV infection.

Keywords: Pseudorabies virus; immunopathogenesis; neuroinflammation; neuropathic itch; neuropathogenesis; non-natural hosts; swine.

Figure 1

Schematic representation of the pathogenesis of PRV in the adult pig. (1) PRV first replicates in the epithelial cells of the URT; (a) PRV infection; (b) viral spread within the respiratory epithelium and viral shedding; (c) PRV breaches the basement membrane via protease activity and penetrates the lamina propria; (d) PRV reaches the draining lymph nodes and blood circulation; (e) PRV enters nerve endings of the PNS, including those coming from the trigeminal ganglia (TG) and spreads in the retrograde direction to the ganglia. (2) PRV establishes latency in TG neurons. (3) PRV replicates in the draining lymph nodes and establishes a cell-free and/or cell-associated viremia in PBMCs (mainly monocytes). (4) Via a cell-associated viremia in monocytes, PRV is transported to the placenta where it initiates a secondary replication in the endothelial cells lining the blood vessels of this organ. Purple = respiratory tract; red = blood circulation; orange = lymph nodes; yellow = TG; blue = uterus.

Figure 2

Schematic representation of the pathogenesis of PRV in a non-natural host, the dog. (1) PRV first replicates in the epithelium of the URT; (a) PRV infection; (b) viral spread within the respiratory epithelium and viral shedding; (c) PRV enters nerve endings of the PNS, including those coming from the TG and spreads in the retrograde direction to the ganglia. (2) PRV initiates a productive infection in TG neurons; (a) PRV replicates in cell bodies of TG neurons; (b) New progeny virions can further spread in the anterograde direction and infect the CNS (brainstem). Purple = respiratory tract; yellow = TG.

Figure 3

Model of PRV-induced neuropathic itch in non-natural hosts. (1) (a) Efficient viral replication and spread of PRV in the respiratory epithelium; (b) PRV particles activate axons terminals of sensory PNS neurons; (c) Activated sensory PNS neurons trigger inflammatory signaling pathways and produce pro-inflammatory cytokines that are released in PNS neurons and locally at axon terminals. (2) (d) Efficient PRV replication in cell bodies of PNS neurons and release of new progeny virions; (e) Spontaneous hyperexcitability of neurons and increase of action potential firing as well as (f) reseeding of new progeny virions back to the epithelium increases electrical coupling of axons and contributes to the pruritus; (b) Amplification of the inflammatory response in PNS neurons; (h) The production of pro-inflammatory cytokines in PNS neurons attract neutrophils and other immune cells to the site of infection and propagate the neuroinflammation. (3) (i) Release of neuropeptides from activated PNS neurons stimulate excitative interneurons in the dorsal horn of the spinal cord; (j) The excitation spreads to spinothalamic tract neurons, which in turn send neuroinflammatory itch signals to the brain; (k) These signals are relayed and processed in the somatosensory cortex. (4) The central itch inhibition pathways are likely dampened or disabled, resulting in an unstoppable pruritus.