Elevated PrPC expression predisposes to increased HSV-1 pathogenicity.
PrPC is a ubiquitously expressed glycophos-phatidylinositol-linked cell-surface glycoprotein found primarily in neural tissue. Although its normal function has not been established, there is evidence suggesting that PrPC is involved in cell signalling and cellular homeostasis. This suggests that variation in neuronal expression levels of this protein contributes towards pathogenicity induced by neurotropic agents. We have investigated the pathological response to infection with herpes simplex virus type-1 (HSV-1) in strains of mice that express different levels of PrPC. Prnp-/- mice fail to express PrPC due to an interruption in the open reading frame of the Prnp gene, whilst tg19 and tga20 mice express approximately 5 and 10 times more PrPC protein, respectively, than wild-type animals. Mice that express normal or increased levels of PrPC protein were more susceptible to acute HSV-1 infection than Prnp-/- mice. Following ear pinna inoculation with HSV-1 SC16, the order of susceptibility was tga20>tg19>wild-type>Prnp-/-. This trend was reversed when latent virus was assessed. Prnp-/- mice expressed significantly higher levels of latency-associated transcript-positive neurons in various tissues when compared with wild-type, tg19 and tga20 mice. Collectively, our data show that acute HSV-1 replication proceeds more efficiently in neuronal tissue that expresses PrPC protein and lends support to the view that this protein is involved in regulation of neurotropic viral pathogenesis. This suggests that interference of PrPC expression, or possible biochemical pathways associated with its function, may serve as an effective means of limiting the pathogenesis of acute HSV-1 infection.
Centre for Veterinary Science, Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 OES, UK.
Alana M
AM
Thackray
Raymond
R
Bujdoso
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001835:Body Weight; D001933:Brain Stem / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology; D020022:Genetic Predisposition to Disease; D006561:Herpes Simplex / Q000378:metabolism* / Q000821:virology; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000472:pathogenicity*; D006651:Histocytochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000821:virology; D018621:PrPC Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D017735:Virus Latency / Q000276:immunology
D000914:Antibodies, Viral; D018621:PrPC Proteins