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Journal of Virology, February 2007, p. 1305-1312, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01926-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Preferential Activation of Toll-Like Receptor Nine by CD46-Utilizing Adenoviruses

Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037

Received 4 September 2006/ Accepted 6 November 2006

Adenoviruses (Ads) are responsible for respiratory, ocular, and gastrointestinal illnesses in humans. While the majority of serotypes utilize coxsackievirus-adenovirus receptor (CAR) as their primary attachment receptor, subgroup B and subgroup D Ad37 serotypes use CD46. Given the propensity of Ad vectors to activate host immune responses, we sought to investigate their potential for type I interferon induction. We found that CD46 Ads were capable of alpha interferon (IFN-) induction by peripheral blood mononuclear cells and that plasmacytoid dendritic cells (pDCs) were the principal producers of this cytokine. IFN- induction correlated with the permissivity of pDCs to CD46- but not CAR-utilizing Ad serotypes. A role for Toll-like receptor 9 (TLR9) recognition of Ad was supported by the requirement for viral DNA and efficient endosomal acidification and by the ability of a TLR9-inhibitory oligonucleotide to attenuate IFN- induction. Cell lines expressing TLR9 that are permissive to infection by both CAR- and CD46-utilizing serotypes showed a preferential induction of TLR9-mediated events by CD46-utilizing Ads. Specifically, the latter virus types induced higher levels of cytokine expression and NF-B activation in HeLa cells than CAR-dependent Ad types, despite equivalent infection rates. Therefore, infectivity alone is not sufficient for TLR9 activation, but this activation instead is regulated by a specific receptor entry pathway. These data reveal a novel mode of host immune recognition of Ad with implications for Ad pathogenesis and for the use of unconventional Ad vectors for gene delivery and vaccine development.

Published ahead of print on 15 November 2006.

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