Quick Search:

uzh logo
Browse by:

Zurich Open Repository and Archive

Maintenance: Tuesday, July the 26th 2016, 07:00-10:00

ZORA's new graphical user interface will be relaunched (For further infos watch out slideshow ZORA: Neues Look & Feel). There will be short interrupts on ZORA Service between 07:00am and 10:00 am. Please be patient.

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-9855

Fejer, G; Drechsel, L; Liese, J; Schleicher, U; Ruzsics, Z; Imelli, N; Greber, U F; Keck, S; Hildenbrand, B; Krug, A; Bogdan, C; Freudenberg, M A (2008). Key role of splenic myeloid DCs in the IFN-alphabeta response to adenoviruses in vivo. PLoS Pathogens, 4(11):e1000208.

View at publisher


The early systemic production of interferon (IFN)-alphabeta is an essential component of the antiviral host defense mechanisms, but is also thought to contribute to the toxic side effects accompanying gene therapy with adenoviral vectors. Here we investigated the IFN-alphabeta response to human adenoviruses (Ads) in mice. By comparing the responses of normal, myeloid (m)DC- and plasmacytoid (p)DC-depleted mice and by measuring IFN-alphabeta mRNA expression in different organs and cells types, we show that in vivo, Ads elicit strong and rapid IFN-alphabeta production, almost exclusively in splenic mDCs. Using knockout mice, various strains of Ads (wild type, mutant and UV-inactivated) and MAP kinase inhibitors, we demonstrate that the Ad-induced IFN-alphabeta response does not require Toll-like receptors (TLR), known cytosolic sensors of RNA (RIG-I/MDA-5) and DNA (DAI) recognition and interferon regulatory factor (IRF)-3, but is dependent on viral endosomal escape, signaling via the MAP kinase SAPK/JNK and IRF-7. Furthermore, we show that Ads induce IFN-alphabeta and IL-6 in vivo by distinct pathways and confirm that IFN-alphabeta positively regulates the IL-6 response. Finally, by measuring TNF-alpha responses to LPS in Ad-infected wild type and IFN-alphabetaR(-/-) mice, we show that IFN-alphabeta is the key mediator of Ad-induced hypersensitivity to LPS. These findings indicate that, like endosomal TLR signaling in pDCs, TLR-independent virus recognition in splenic mDCs can also produce a robust early IFN-alphabeta response, which is responsible for the bulk of IFN-alphabeta production induced by adenovirus in vivo. The signaling requirements are different from known TLR-dependent or cytosolic IFN-alphabeta induction mechanisms and suggest a novel cytosolic viral induction pathway. The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease.


65 citations in Web of Science®
63 citations in Scopus®
Google Scholar™



206 downloads since deposited on 23 Jan 2009
47 downloads since 12 months

Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Date:14 November 2008
Deposited On:23 Jan 2009 15:25
Last Modified:05 Apr 2016 12:48
Publisher:Public Library of Science (PLoS)
Publisher DOI:10.1371/journal.ppat.1000208
PubMed ID:19008951

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page