Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Author:

Baglio S. Rubina,van Eijndhoven Monique A. J.,Koppers-Lalic Danijela,Berenguer Jordi,Lougheed Sinéad M.,Gibbs Susan,Léveillé Nicolas,Rinkel Rico N. P. M.,Hopmans Erik S.,Swaminathan Sankar,Verkuijlen Sandra A. W. M.,Scheffer George L.,van Kuppeveld Frank J. M.,de Gruijl Tanja D.,Bultink Irene E. M.,Jordanova Ekaterina S.,Hackenberg Michael,Piersma Sander R.,Knol Jaco C.,Voskuyl Alexandre E.,Wurdinger Thomas,Jiménez Connie R.,Middeldorp Jaap M.,Pegtel D. Michiel

Abstract

Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein–Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viral- and exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non–cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host–pathogen stand-off and may promote inflammatory disease.

Funder

Dutch arthritis foundation

Association for International Cancer Research

KWF Kankerbestrijding

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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