Preferential Activation of Toll-Like Receptor Nine by CD46-Utilizing Adenoviruses
- 1 February 2007
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (3) , 1305-1312
- https://doi.org/10.1128/jvi.01926-06
Abstract
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-alpha) induction by peripheral blood mononuclear cells and that plasmacytoid dendritic cells (pDCs) were the principal producers of this cytokine. IFN-alpha 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-alpha 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-kappaB 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.Keywords
This publication has 67 references indexed in Scilit:
- Herpes Simplex Virus Encephalitis in Human UNC-93B DeficiencyScience, 2006
- Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primatesThe Journal of Experimental Medicine, 2006
- TLR signalingCell Death & Differentiation, 2006
- Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Nature, 2005
- Role of Viral Vectors and Virion Shells in Cellular Gene ExpressionMolecular Therapy, 2004
- TLR9 signals after translocating from the ER to CpG DNA in the lysosomeNature Immunology, 2004
- Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T CellsThe Journal of Experimental Medicine, 2003
- The Interaction between the Fiber Knob Domain and the Cellular Attachment Receptor Determines the Intracellular Trafficking Route of AdenovirusesJournal of Virology, 2003
- Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartmentsEuropean Journal of Immunology, 2002
- CpG islands as gene markers in the vertebrate nucleusTrends in Genetics, 1987