Histamine Is Responsible for the Neuropathic Itch Induced by the Pseudorabies Virus Variant in a Mouse Model
Bing Wang1, Hongxia Wu1, Hansong Qi1
1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 678 Haping Road, Harbin 150069, China.
Abstract:
Pseudorabies virus (PRV) is the causative agent of pseudorabies (PR). It can infect a wide range of mammals. PRV infection can cause severe acute neuropathy (the so-called "mad itch") in nonnatural hosts. PRV can infect the peripheral nervous system (PNS), where it can establish a quiescent, latent infection. The dorsal root ganglion (DRG) contains the cell bodies of the spinal sensory neurons, which can transmit peripheral sensory signals, including itch and somatic pain. Little attention has been paid to the underlying mechanism of the itch caused by PRV in nonnatural hosts. In this study, a mouse model of the itch caused by PRV was elaborated. BALB/c mice were infected intramuscularly with 105 TCID50 of PRV TJ. The frequency of the bite bouts and the durations of itch were recorded and quantified. The results showed that the PRV-infected mice developed spontaneous itch at 32 h postinfection (hpi). The frequency of the bite bouts and the durations of itch were increased over time. The mRNA expression levels of the receptors and the potential cation channels that are relevant to the itch-signal transmission in the DRG neurons were quantified. The mRNA expression levels of tachykinin 1 (TAC1), interleukin 2 (IL-2), IL-31, tryptases, tryptophan hydroxylase 1 (TPH1), and histidine decarboxylase (HDC) were also measured by high-throughput RNA sequencing and real-time reverse transcription PCR. The results showed that the mean mRNA level of the HDC in the DRG neurons isolated from the PRV-infected mice was approximately 25-fold higher than that of the controls at 56 hpi. An immunohistochemistry (IHC) was strongly positive for HDC in the DRG neurons of the PRV-infected mice, which led to the high expression of histamine at the injected sites. The itch of the infected mice was inhibited by chlorphenamine hydrogen maleate (an antagonist for the histamine H1 receptor) in a dose-dependent manner. The mRNA and protein levels of the HDC in the DRG neurons were proportional to the severity of the itch induced by different PRV strains. Taken together, the histamine synthesized by the HDC in the DRG neurons was responsible for the PRV-induced itch in the mice.
Insights
Pseudorabies virus (PRV) causes severe itch in mammals by increasing histamine production in nerve cells. Blocking histamine receptors effectively reduces this PRV-induced itch, revealing a key mechanism.
Area of Science:
- Virology and Neuroscience
- Mammalian Pathogen Research
- Itch and Pain Signaling Mechanisms
Background:
- Pseudorabies virus (PRV) causes 'mad itch' neuropathy in non-natural hosts.
- PRV establishes latent infections in the peripheral nervous system, including dorsal root ganglia (DRG).
- The mechanism of PRV-induced itch in non-natural hosts remains poorly understood.
Purpose of the Study:
- To investigate the underlying mechanism of PRV-induced itch in a mouse model.
- To identify molecular pathways in DRG neurons involved in PRV-mediated itch.
- To explore potential therapeutic targets for PRV-induced pruritus.
Main Methods:
- Established a mouse model by intramuscularly infecting BALB/c mice with PRV TJ.
- Quantified itch behaviors (bite bouts, duration) and analyzed mRNA expression in DRG neurons using RNA sequencing and RT-PCR.
- Utilized immunohistochemistry (IHC) to detect protein expression and tested histamine receptor antagonists for itch inhibition.
Main Results:
- PRV-infected mice exhibited spontaneous itch starting at 32 hours post-infection, increasing over time.
- Significant upregulation of histidine decarboxylase (HDC) mRNA (approx. 25-fold) and protein was observed in DRG neurons.
- Histamine levels were elevated at injection sites, and itch was dose-dependently inhibited by a histamine H1 receptor antagonist.
Conclusions:
- Histamine synthesized by HDC in DRG neurons is directly responsible for PRV-induced itch.
- The severity of itch correlates with HDC expression levels induced by different PRV strains.
- Targeting histamine signaling offers a potential therapeutic strategy for PRV-associated pruritus.
