TY - JOUR
T1 - Sensing of latent EBV infection through exosomal transfer of 5'pppRNA
AU - Baglio, S.R.
AU - van Eijndhoven, M.A.J.
AU - Koppers-Lalic, D.
AU - Berenguer, J.
AU - Lougheed, S.M.
AU - Gibbs, S.
AU - Léveillé, N.
AU - Rinkel, R.N.P.M.
AU - Hopmans, E.S.
AU - Swaminathan, S.
AU - Verkuijlen, S.A.W.M.
AU - Scheffer, G.L.
AU - van Kuppeveld, F.J.M.
AU - de Gruijl, T.D.
AU - Bultink, I.E.M.
AU - Jordanova, E.S.
AU - Hackenberg, M.
AU - Piersma, S.R.
AU - Knol, J.C.
AU - Voskuyl, A.E.
AU - Wurdinger, T.
AU - Jiménez, C.R.
AU - Middeldorp, J.M.
AU - Pegtel, D.M.
N1 - With supporting information
PY - 2016/2/2
Y1 - 2016/2/2
N2 - 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 viraland 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.
AB - 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 viraland 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.
KW - Biological Transport
KW - Dendritic Cells
KW - EBV-EBER
KW - Epstein-Barr Virus Infections
KW - Exosomes
KW - Herpesvirus 4, Human
KW - Humans
KW - Innate Sensing
KW - Journal Article
KW - Proteome
KW - RNA, Viral
KW - Research Support, Non-U.S. Gov't
KW - Skin Inflammation
UR - http://www.scopus.com/inward/record.url?scp=84956629623&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1518130113
DO - https://doi.org/10.1073/pnas.1518130113
M3 - Article
C2 - 26768848
SN - 0027-8424
VL - 113
SP - E587-E596
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 5
ER -
