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

被引：134

作者：

Baglio, S. Rubina ^{[1
]}

van Eijndhoven, Monique A. J. ^{[1
]}

Koppers-Lalic, Danijela ^{[1
,2
]}

Berenguer, Jordi ^{[2
]}

Lougheed, Sinead M. ^{[3
]}

Gibbs, Susan ^{[4
,5
,6
]}

Leveille, Nicolas ^{[7
]}

Rinkel, Rico N. P. M. ^{[8
]}

Hopmans, Erik S. ^{[1
]}

Swaminathan, Sankar ^{[9
,10
]}

Verkuijlen, Sandra A. W. M. ^{[1
]}

Scheffer, George L. ^{[1
]}

van Kuppeveld, Frank J. M. ^{[11
]}

de Gruijl, Tanja D. ^{[3
]}

Bultink, Irene E. M. ^{[12
]}

Jordanova, Ekaterina S. ^{[13
]}

Hackenberg, Michael ^{[14
]}

Piersma, Sander R. ^{[15
]}

Knol, Jaco C. ^{[15
]}

Voskuyl, Alexandre E. ^{[12
]}

Wurdinger, Thomas ^{[2
]}

Jimenez, Connie R. ^{[15
]}

Middeldorp, Jaap M. ^{[1
]}

Pegtel, D. Michiel ^{[1
]}

机构：

[1] Vrije Univ Amsterdam, Univ Med Ctr, Canc Ctr Amsterdam, Dept Pathol, NL-1081 HV Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Univ Med Ctr, Canc Ctr Amsterdam, Dept Neurosurg, NL-1081 HV Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Univ Med Ctr, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands

[4] Vrije Univ Amsterdam, Univ Med Ctr, Canc Ctr Amsterdam, Dept Dermatol, NL-1081 HV Amsterdam, Netherlands

[5] Univ Amsterdam, Acad Ctr Dent Amsterdam, Dept Oral Cell Biol, NL-1081 HZ Amsterdam, Netherlands

[6] Vrije Univ Amsterdam, NL-1081 HZ Amsterdam, Netherlands

[7] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, CEMM, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[8] Vrije Univ Amsterdam, Univ Med Ctr, Canc Ctr Amsterdam, Dept Otolaryngol, NL-1081 HV Amsterdam, Netherlands

[9] Univ Utah, Dept Med, Salt Lake City, UT 84132 USA

[10] George E Wahlen VA Med Ctr, Salt Lake City, UT 84132 USA

[11] Univ Utrecht Hosp, Fac Vet Med, Dept Infect Dis & Immunol, NL-3584 CL Utrecht, Netherlands

[12] Vrije Univ Amsterdam, Univ Med Ctr, Amsterdam Rheumatol & Immunol Ctr, Dept Rheumatol, NL-1081 HV Amsterdam, Netherlands

[13] Vrije Univ Amsterdam, Univ Med Ctr, Ctr Gynaecol Oncol Amsterdam, Dept Obstet & Gynecol, NL-1081 HV Amsterdam, Netherlands

[14] Univ Granada, Dept Genet, E-18071 Granada, Spain

[15] Vrije Univ Amsterdam, Univ Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 05期

关键词：

exosomes; EBV-EBER1; innate sensing; dendritic cells; skin inflammation; EPSTEIN-BARR-VIRUS; PLASMACYTOID DENDRITIC CELLS; RIG-I; SMALL RNA; INTERFERON-ALPHA; INNATE IMMUNITY; LUPUS-ERYTHEMATOSUS; INDUCED APOPTOSIS; NONCODING RNAS; VIRAL MIRNAS;

D O I：

10.1073/pnas.1518130113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：E587 / E596

页数：10

共 71 条

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