engleski

Complex viral regulation of PVR by MCMV to avoid NK cell recognition

Human cytomegalovirus (HCMV) is ubiquitous beta-herpesvirus that infects the majority of human populations. Murine cytomegalovirus (MCMV) is most widely used model for HCMV pathogenesis since the two viruses are genetically related and share many biological and pathological features. Both viruses cause persistent infection that lasts for life thanks to a plethora of viral immunoevasion genes targeted at both innate and adaptive arms of the immune system. Among many other immunoreceptor ligands targeted by HCMV is CD155 (PVR). PVR serves as a ligand for three NK and T cell receptors: activating receptors CD226 (DNAM-1) and CD96 (TACTILE) and inhibitory receptor TIGIT. Previously it was shown that HCMV blocks the surface expression of PVR. Here we show negative regulation of PVR by MCMV and attempt to dissect the mechanisms behind the regulation. Infection by MCMV causes increased transcription of the PVR gene however infected cells show diminished amounts of surface PVR. Using multiple viral deletion mutants we show that MCMV has dedicated two viral genes towards regulation of PVR surface expression: m154 and m20. Deletion of either m154 or m20 MCMV ORFs prevented downregulation and resulted in viral attenuation in vivo, while deletion of both ORFs resulted in upregulation of PVR on the cell surface. While m20 regulates the maturation of PVR, mechanism of action of m154 is still unknown. m20 gene region displays a very complex transcriptional profile with multiple overlapping 3’ co-terminal transcripts that show distinct temporal expression. Recent work on ribosomal footprinting in HCMV showed that such complex transcriptional profiles are more widespread among cytomegaloviruses than previously thought. In our transcriptomic study, we have identified several loci in MCMV genome that display similar expression profile. Overlapping 3’ co-terminal transcripts have the potential to encode different proteins either by using different ORFs or by producing N-terminal truncations. Using a panel of deletion mutants we have managed to identify transcript responsible for PVR regulation via ER retention.

pvr virus cytomegalovirus downregulation MCMV

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