The Pseudorabies Virus Glycoprotein gE/gI Complex Suppresses Type I Interferon Production by Plasmacytoid Dendritic Cells

Lamote, Jochen; Kestens, Manon; Waesberghe, Cliff Van; Delva, Jonas L.; Pelsmaeker, Steffi De; Devriendt, Bert; Favoreel, Herman

doi:10.1128/jvi.02276-16

Cited by 33 publications

(46 citation statements)

References 64 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a result, more virus particles may invade axon terminals of the DRG neurons and replicate in the cell bodies. A recent study showed that PRV-Becker inhibits the IFN response in swine plasmacytoid DCs, while PRV-Bartha elicits a much more robust type I IFN response in these cells (66). This difference was attributed to a deletion of the glycoprotein gE/gI gene complex in the genome of Bartha.…”

Section: Discussionmentioning

confidence: 99%

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Laval

Vernejoul

Cleemput

et al. 2018

J Virol

View full text Add to dashboard Cite

Pseudorabies virus (PRV) is an alphaherpesvirus that infects the peripheral nervous system (PNS). The natural host of PRV is the swine, but it can infect most mammals, including cattle, rodents, and dogs. In these nonnatural hosts, PRV always causes a severe acute and lethal neuropathy called the "mad itch," which is uncommon in swine. Thus far, the pathophysiological and immunological processes leading to the development of the neuropathic itch and the death of the animal are unclear. Using a footpad inoculation model, we established that mice inoculated with PRV-Becker (virulent strain) develop a severe pruritus in the foot and become moribund at 82 h postinoculation (hpi). We found necrosis and inflammation with a massive neutrophil infiltration only in the footpad and dorsal root ganglia (DRGs) by hematoxylin and eosin staining. PRV load was detected in the foot, PNS, and central nervous system tissues by quantitative reverse transcription-PCR. Infected mice had elevated plasma levels of proinflammatory cytokines (interleukin-6 [IL-6] and granulocyte colony-stimulating factor [G-CSF]) and chemokines (Gro-1 and monocyte chemoattractant protein 1). Significant IL-6 and G-CSF levels were detected in several tissues at 82 hpi. High plasma levels of C-reactive protein confirmed the acute inflammatory response to PRV-Becker infection. Moreover, mice inoculated with PRV-Bartha (attenuated, live vaccine strain) did not develop pruritus at 82 hpi. PRV-Bartha also replicated in the PNS, and the infection spread further in the brain than PRV-Becker. PRV-Bartha infection did not induce the specific and lethal systemic inflammatory response seen with PRV-Becker. Overall, we demonstrated the importance of inflammation in the clinical outcome of PRV infection in mice and provide new insights into the process of PRV-induced neuroinflammation.IMPORTANCE Pseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens such as herpes simplex virus 1 and varicella-zoster virus (VZV). The natural host of PRV is the swine, but it can infect most mammals. In susceptible animals other than pigs, PRV infection always causes a characteristic lethal pruritus known as the "mad itch." The role of the immune response in the clinical outcome of PRV infection is still poorly understood. Here, we show that a systemic host inflammatory response is responsible for the severe pruritus and acute death of mice infected with virulent PRV-Becker but not mice infected with attenuated strain PRV-Bartha. In addition, we identified IL-6 and G-CSF as two main cytokines that play crucial roles in the regulation of this process. Our findings give new insights into neuroinflammatory diseases and strengthen further the similarities between VZV and PRV infections at the level of innate immunity. Citation Laval K, Vernejoul JB, Van Cleemput J, Koyuncu OO, Enquist LW. 2018. Virulent pseudorabies virus infection induces a specific and lethal systemic inflammatory response in mice. J Virol 92:e01614-18. https://doi.org/10 .1128/JVI.01614-18. Editor Ric...

show abstract

Section: Discussionmentioning

confidence: 99%

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Laval

Vernejoul

Cleemput

et al. 2018

J Virol

View full text Add to dashboard Cite

show abstract

“…In addition, Lamote and colleagues demonstrated that PRV-Becker inhibits the IFN response in swine dendritic cells while PRV-Bartha induces a strong type I IFN response in these cells. This difference was attributed to the absence of the immunomodulatory glycoprotein gE/gI gene complex, in the genome of Bartha [137]. So far, the level of type I IFN has not been quantified in the swine URT and compared between PRV-Becker and PRV-Bartha infections.…”

Section: Why Prv-infected Swine Do Not Itchmentioning

confidence: 99%

The Neuropathic Itch Caused by Pseudorabies Virus

Laval

Enquist

2020

Pathogens

View full text Add to dashboard Cite

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.

show abstract

“…For example, virulent PRV-Becker infection suppresses the expression of most IFNβ-stimulated genes in primary rat fibroblasts through inhibition of STAT1 tyrosine phosphorylation [23]. In addition, another study showed that PRV-Becker infection inhibits the IFN response in swine plasmacytoid dendritic cells (pDCs), while the attenuated vaccine strain PRV-Bartha elicits a much more robust type I IFN response in these cells [24]. This difference was attributed to a deletion of the glycoprotein gE/gI gene complex in the PRV Bartha genome.…”

Section: Introductionmentioning

confidence: 99%

Alphaherpesvirus infection of mice primes PNS neurons to an inflammatory state regulated by TLR2 and type I IFN signaling

et al. 2019

View full text Add to dashboard Cite

Pseudorabies virus (PRV), an alphaherpesvirus closely related to Varicella-Zoster virus (VZV) and Herpes simplex type 1 (HSV1) infects mucosa epithelia and the peripheral nervous system (PNS) of its host. We previously demonstrated that PRV infection induces a specific and lethal inflammatory response, contributing to severe neuropathy in mice. So far, the mechanisms that initiate this neuroinflammation remain unknown. Using a mouse footpad inoculation model, we found that PRV infection rapidly and simultaneously induces high G-CSF and IL-6 levels in several mouse tissues, including the footpad, PNS and central nervous system (CNS) tissues. Interestingly, this global increase occurred before PRV had replicated in dorsal root ganglia (DRGs) neurons and also was independent of systemic inflammation. These high G-CSF and IL-6 levels were not caused by neutrophil infiltration in PRV infected tissues, as we did not detect any neutrophils. Efficient PRV replication and spread in the footpad was sufficient to activate DRGs to produce cytokines. Finally, by using knockout mice, we demonstrated that TLR2 and IFN type I play crucial roles in modulating the early neuroinflammatory response and clinical outcome of PRV infection in mice. Overall, these results give new insights into the initiation of virus-induced neuroinflammation during herpesvirus infections.

show abstract

The Pseudorabies Virus Glycoprotein gE/gI Complex Suppresses Type I Interferon Production by Plasmacytoid Dendritic Cells

Cited by 33 publications

References 64 publications

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

The Neuropathic Itch Caused by Pseudorabies Virus

Alphaherpesvirus infection of mice primes PNS neurons to an inflammatory state regulated by TLR2 and type I IFN signaling

Contact Info

Product

Resources

About