Pseudorabies Virus Infection Causes Downregulation of Ligands for the Activating NK Cell Receptor NKG2D.

Sofie Denaeghel,Herman W Favoreel,Cliff Van Waesberghe,Steffi De Pelsmaeker

doi:10.3390/v13020266

Abstract

Herpesviruses display a complex and carefully balanced interaction with important players in the antiviral immune response of immunocompetent natural hosts, including natural killer (NK) cells. With regard to NK cells, this delicate balance is illustrated on the one hand by severe herpesvirus disease reported in individuals with NK cell deficiencies and on the other hand by several NK cell evasion strategies described for herpesviruses. In the current study, we report that porcine cells infected with the porcine alphaherpesvirus pseudorabies virus (PRV) display a rapid and progressive downregulation of ligands for the major activating NK cell receptor NKG2D. This downregulation consists both of a downregulation of NKG2D ligands that are already expressed on the cell surface of an infected cell and an inhibition of cell surface expression of newly expressed NKG2D ligands. Flow cytometry and RT-qPCR assays showed that PRV infection results in downregulation of the porcine NKG2D ligand pULBP1 from the cell surface and a very substantial suppression of mRNA expression of pULBP1 and of another potential NKG2D ligand, pMIC2. Furthermore, PRV-induced NKG2D ligand downregulation was found to be independent of late viral gene expression. In conclusion, we report that PRV infection of host cells results in a very pronounced downregulation of ligands for the activating NK cell receptor NKG2D, representing an additional NK evasion strategy of PRV.

Highlights

Members of the natural killer group 2 (NKG2) receptor family all are type II transmembrane glycoproteins, belonging to the C-type lectin-like family [1]
To determine if pseudorabies virus (PRV) infection in swine kidney (SK) cells affects the binding of NKG2D to the cell surface, we investigated the binding of recombinant NKG2D to the surface of mock- or PRV-infected Swine Kidney (SK) cells
In line with what is known for human NKG2D ligands like MICA [31], we found that NKG2D ligands on the cell surface of porcine SK cells are trypsin- and accutase-sensitive and cannot be detected immediately after detachment of adherent cells via trypsinization

Summary

Introduction

Members of the natural killer group 2 (NKG2) receptor family all are type II transmembrane glycoproteins, belonging to the C-type lectin-like family [1]. Only two ligands have been described far, porcine MIC2 (pMIC2) and porcine ULPB1 (pULBP1) The latter shows a 35%–54% amino acid sequence homology to human ULPBs, whereas the former shows an amino acid sequence homology of 54% to human MICA [14,15,16,17]. Both molecules have been reported to have the ability to bind (human) NKG2D, and it appears likely that there are additional, yet unidentified porcine ligands for NKG2D [17]

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Results

Conclusion