Deleting two amino acids in glycoprotein gI of pseudorabies virus decreases virulence and neurotropism for pigs, but does not affect immunogenicity

Jacobs, Liesbeth; Mulder, W.A.; Oirschot, J.T. van; Gielkens, A. L. J.; Kimman, Tjeerd G.

doi:10.1099/0022-1317-74-10-2201

Cited by 55 publications

(28 citation statements)

References 20 publications

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“…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.…”

mentioning

confidence: 70%

“…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).…”

Section: In Animal Models Of Infection Glycoprotein E (Ge) Is Requirmentioning

confidence: 99%

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

McGraw

Friedman

2009

J Virol

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In animal models of infection, glycoprotein E (gE) is required for efficient herpes simplex virus type 1 (HSV-1) spread from the inoculation site to the cell bodies of innervating neurons (retrograde direction).Retrograde spread in vivo is a multistep process, in that HSV-1 first spreads between epithelial cells at the inoculation site, then infects neurites, and finally travels by retrograde axonal transport to the neuron cell body. To better understand the role of gE in retrograde spread, we used a compartmentalized neuron culture system, in which neurons were infected in the presence or absence of epithelial cells. We found that gE-deleted HSV-1 (NS-gEnull) retained retrograde axonal transport activity when added directly to neurites, in contrast to the retrograde spread defect of this virus in animals. To better mimic the in vivo milieu, we overlaid neurites with epithelial cells prior to infection. In this modified system, virus infects epithelial cells and then spreads to neurites, revealing a 100-fold retrograde spread defect for NS-gEnull. We measured the retrograde spread defect of NS-gEnull from a variety of epithelial cell lines and found that the magnitude of the spread defect from epithelial cells to neurons correlated with epithelial cell plaque size defect, indicating that gE plays a similar role in both types of spread. Therefore, gE-mediated spread between epithelial cells and neurites likely explains the retrograde spread defect of gE-deleted HSV-1 in vivo.Herpes simplex virus type 1 (HSV-1) is an alphaherpesvirus that characteristically infects skin and mucosal surfaces before spreading to sensory neurons, where it establishes a lifelong persistent infection. The virus periodically returns to the periphery via sensory axons and causes recurrent lesions as well as asymptomatic shedding. This life cycle requires viral transport along axons in two directions: toward the neuron cell body (retrograde direction) and away from the neuron cell body (anterograde direction).Many studies of alphaherpesvirus neuronal spread have focused on pseudorabies virus (PRV), a virus whose natural host is the pig. 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). In the murine flank model, wild-type (WT) virus replicates in the skin and then infects sensory neurons and spreads in a retrograde direction to the dorsal root ganglia (DRG). 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.HSV-1 gE is a 552-amino-...

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confidence: 70%

Section: In Animal Models Of Infection Glycoprotein E (Ge) Is Requirmentioning

confidence: 99%

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

McGraw

Friedman

2009

J Virol

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“…PRV-Bartha DNA carries a 3.4-kb deletion in the unique short region of the genome, removing sequences coding for gI, gE, US9, and US2 (36,41,46) as well point mutations within the glycoprotein C (gC), gM, and UL21 genes (16,32,37,54). PRV-Bartha shows robust growth on most cell lines but is remarkably reduced for virulence in every permissive species tested (1,2,8,12,(27)(28)(29)(30)42). Even at high inoculating doses, PRV-Bartha-infected animals survive longer with markedly reduced symptoms compared to similar infection by wild-type virus (8).…”

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confidence: 99%

Transcriptome Signature of Virulent and Attenuated Pseudorabies Virus-Infected Rodent Brain

Paulus

Sollars

Pickard

et al. 2006

J Virol

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Mammalian alphaherpesviruses normally establish latent infections in ganglia of the peripheral nervous system in their natural hosts. Occasionally, however, these viruses spread to the central nervous system (CNS), where they cause damaging, often fatal, infections. Attenuated alphaherpesvirus derivatives have been used extensively as neuronal circuit tracers in a variety of animal models. Their circuit-specific spread provides a unique paradigm to study the local and global CNS response to infection. Thus, we systematically analyzed the host gene expression profile after acute pseudorabies virus (PRV) infection of the CNS using Affymetrix GeneChip technology. Rats were injected intraocularly with one of three selected virulent and attenuated PRV strains. Relative levels of cellular transcripts were quantified from hypothalamic and cerebellar tissues at various times postinfection. The number of cellular genes responding to infection correlated with the extent of virus dissemination and relative virulence of the PRV strains. A total of 245 out of 8,799 probe sets, corresponding to 182 unique cellular genes, displayed increased expression ranging from 2-to more than 100-fold higher than in uninfected tissue. Over 60% thereof were categorized as immune, proinflammatory, and other cellular defense genes. Additionally, a large fraction of infection-induced transcripts represented cellular stress responses, including glucocorticoid-and redox-related pathways. This is the first comprehensive in vivo analysis of the global transcriptional response of the mammalian CNS to acute alphaherpesvirus infection. The differentially regulated genes reported here are likely to include potential diagnostic and therapeutic targets for viral encephalitides and other neurodegenerative or neuroinflammatory diseases.

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“…It is one of PrV virulence determinants and a non-essential protein for in vitro replication as well (Van et al, 1990). When the gE gene is deleted, the propagation and antigenicity of PrV are not affected, but its virulence is reduced greatly (Jacobs et al, 1993;Nauwynck, 1997). On the other hand, gE is present in almost all examined PrV field isolates, and the natural infection always gives rise to detectable antibodies against gE.…”

Section: Methodsmentioning

confidence: 96%

Association analysis between pseudorabies antibody and five single-nucleotide polymorphisms in pigs

Zhang

Jafer

Yuan

et al. 2009

Animal

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Pseudorabies has become endemic and represents a widespread problem for pig production in the world, causing great economic losses associated with reproductive failure and neonatal mortality in the pig industry. Most diseases are the results of mutations of functional genes. Single-nucleotide polymorphisms (SNPs) from the coding regions of the mediators of pro-inflammatory responses or other candidate genes in pigs could indicate their potential involvement in susceptibility or resistance to PrV (pseudorabies virus) infection. There have been no previous association studies with candidate host genes that may influence PrV phenotypic traits. In order to perform association studies to identify genes contributing to PrV phenotypes, the genotypes of five SNPs from four genes ( IL10, CXCL12, BAT2 and EHMT2) were determined for 178 sow samples using a high throughput microarray-based methodology. PrV antibodies were tested by enzyme-linked immunosorbent assay (ELISA) to determine whether there was an association between antibody levels and particular genotypes. The association between SNP genotypes and the PrV antibody levels were analysed using the Duncan method of one-way ANOVA procedure using the SAS (Statistical Analysis Systems) software package. The results showed that the glycoprotein E-ELISA antibody level of pigs with genotypes 11(AA) and 12(AG) was significantly higher than in pigs with genotype 22(GG) ( P , 0.05) of SNP in the gene EHMT2-SNP2. The SNP of EHMT2 may be an effective potential tool to identify susceptible and resistant animals when used in conjunction with traditional selection methods.

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Deleting two amino acids in glycoprotein gI of pseudorabies virus decreases virulence and neurotropism for pigs, but does not affect immunogenicity

Cited by 55 publications

References 20 publications

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

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

Transcriptome Signature of Virulent and Attenuated Pseudorabies Virus-Infected Rodent Brain

Association analysis between pseudorabies antibody and five single-nucleotide polymorphisms in pigs

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