Epstein-Barr Virus-Encoded BILF1 Orthologues From Porcine Lymphotropic Herpesviruses Display Common Molecular Functionality
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Infection of immunosuppressed transplant patients with the human γ-herpesvirus Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD), an often fatal complication. Immunosuppressed miniature pigs infected with γ-herpesvirus porcine lymphotropic herpesvirus 1 (PLHV1) develop a similar disease, identifying pigs as a potential preclinical model for PTLD in humans. BILF1 is a G protein-coupled receptor (GPCR) encoded by EBV with constitutive activity linked to tumorigenesis and immunoevasive function downregulating MHC-I. In the present study, we compared BILF1-orthologues encoded by the three known PLHVs (PLHV1-3) with EBV-BILF1 to determine pharmacological suitability of BILF1 orthologues as model system to study EBV-BILF1 druggability. Cell surface localization, constitutive internalization, and MHC-I downregulation as well as membrane proximal constitutive Gαi signaling patterns were conserved across all BILFs. Only subtle differences between the individual BILFs were observed in downstream transcription factor activation. Using Illumina sequencing, PLHV1 was observed in lymphatic tissue from PTLD-diseased, but not non-diseased pigs. Importantly, these tissues showed enhanced expression of PLHV1-BILF1 supporting its involvement in PTLD infection.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 862940 |
| Tidsskrift | Frontiers in Endocrinology |
| Vol/bind | 13 |
| Antal sider | 16 |
| ISSN | 1664-2392 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
The authors would like to thank Florent Xavier Smit for his help on homology model of the human MHC-I and porcine MHC-I molecule. We acknowledge the Core Facility for Integrated Microscopy (CFIM), Faculty of Health and Medical Sciences, University of Copenhagen and their staff, especially Pablo Hernandes-Varas for excellent guidance and support while performing microsopy. We also acknowledge Core Facility for Flow Cytometry and Single Cell Analysis, Faculty of Health and Medical Sciences, University of Copenhagen. We thank Asuka Inoue (Tohoku University, Japan) for supplying CRISPR/Cas9 modified pan KO cells. We also thank prof. dr. Peter Hostnik, who provided PK-15 cells. We would like to thank Magdalena Dobravec, for excellent technical assistance. MM, KS, MMR, MV and VK participate in the European COST Action CA 18133 (ERNEST).
Funding Information:
We acknowledge funding from the Slovenian Research Agency program P4-0053 and PhD funding for MM. This work was also supported by a Short-term scientific mission (STSM) grant from COST Action CA 18133 (ERNEST). Authors participate in the European COST Action CA 18133 (ERNEST). KS was funded by a postdoc grant from the Danish Council for Independent Research. TP and EJJ were funded by the P1-0207 Research Program grant, the J7-1818 Research Project grant to TP and the Z3-2650 postdoctoral fellowship to EJJ from the Slovenian Research Agency. MMR and KS were funded by The European Research council: VIREX (Grant agreement 682549, Call ERC-2105-CoG).
Publisher Copyright:
Copyright © 2022 Mavri, Kubale, Depledge, Zuo, Huang, Breuer, Vrecl, Jarvis, Jovičić, Petan, Ehlers, Rosenkilde and Spiess.
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