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Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):E587-96. doi: 10.1073/pnas.1518130113. Epub 2016 Jan 14.

Sensing of latent EBV infection through exosomal transfer of 5'pppRNA.

Author information

1
Department of Pathology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, 1081 HV Amsterdam, The Netherlands;
2
Department of Pathology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, 1081 HV Amsterdam, The Netherlands; Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
3
Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
4
Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
5
Department of Dermatology, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands; Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University, 1081 HZ Amsterdam, The Netherlands;
6
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1105 AZ Amsterdam, The Netherlands;
7
Department of Otolaryngology, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
8
Department of Medicine, University of Utah and George E. Wahlen VA Medical Center, Salt Lake City, UT 84132;
9
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University Hospital, 3584 CL Utrecht, The Netherlands;
10
Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
11
Department of Obstetrics and Gynecology, Center for Gynaecological Oncology Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;
12
Department of Genetics, University of Granada, 18071 Granada, Spain;
13
Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
14
Department of Pathology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, 1081 HV Amsterdam, The Netherlands; d.pegtel@vumc.nl.

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.

KEYWORDS:

EBV-EBER1; dendritic cells; exosomes; innate sensing; skin inflammation

PMID:
26768848
PMCID:
PMC4747727
DOI:
10.1073/pnas.1518130113
[Indexed for MEDLINE]
Free PMC Article

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