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Journal of Virology, April 2007, p. 4145-4157, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02685-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sensing Infection by Adenovirus: Toll-Like Receptor-Independent Viral DNA Recognition Signals Activation of the Interferon Regulatory Factor 3 Master Regulator{triangledown}

Marcelo Nociari,1 Oksana Ocheretina,1 John W. Schoggins,2 and Erik Falck-Pedersen2*

Weill Medical College of Cornell University, Department of Medicine,1 Department of Microbiology and Immunology, Molecular Biology Graduate Program, New York, New York 100212

Received 5 December 2006/ Accepted 20 January 2007

Infection with adenovirus vectors (AdV) results in rapid activation of innate immunity, which serves the dual purpose of stimulating inflammatory antiviral host defenses and the adaptive immune system. Viral recognition by macrophages, dendritic cells, and other cell types requires an ability to sense the presence of a foreign molecular pattern by "pattern recognition receptors." The nature of the adenoviral sensor, the target ligand of the sensor, and the downstream antiviral signaling response triggered by virus infection have not been defined for this nonenveloped double-stranded DNA (dsDNA) virus. We have identified four critical links involved in AdV recognition by murine antigen-presenting cells (APC) and primary lung fibroblasts: (i) viral recognition occurs chiefly via a Toll-like receptor (TLR)-independent nucleic acid-sensing mechanism recognizing the viral dsDNA genome, (ii) the intact viral particle and capsid proteins are required for efficient intracellular delivery of the viral genome, (iii) delivery of the viral genome triggers interferon regulatory factor 3 (IRF3) phosphorylation, and (iv) IRF3 activation is the required dominant antiviral signaling pathway used by APC, whereas the "primary" involvement of NF-{kappa}B, mitogen-activated protein kinase, or Akt pathways is less prominent. In this study we provide the first direct evidence that infection by a dsDNA virus stimulates an IRF3-mediated interferon and proinflammatory response through a TLR-independent DNA-sensing mechanism.

* Corresponding author. Mailing address: Weill Medical College of Cornell University, Department of Microbiology and Immunology Box 62, 1300 York Ave. New York, NY 10021. Phone: (212) 746-6514. Fax: (212) 746-8587. E-mail: efalckp{at}med.cornell.edu

{triangledown} Published ahead of print on 24 January 2007.

Journal of Virology, April 2007, p. 4145-4157, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02685-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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