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J. Virol. doi:10.1128/JVI.02685-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Sensing infection by Adenovirus: TLR-independent viral DNA recognition signals activation of the IRF3 master regulator

Weill Medical College of Cornell University, Department of Medicine, Department of Microbiology and Immunology Molecular Biology Graduate Program, New York, New York 10021

^* To whom correspondence should be addressed. Email: efalckp{at}med.cornell.edu.

	Abstract

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, DCs, 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 non-enveloped dsDNA virus. We have identified four critical links involved in AdV recognition by murine antigen presenting cells (APCs) and primary lung fibroblasts: (1) viral recognition occurs chiefly via a TLR-independent nucleic acid sensing mechanism recognizing the viral dsDNA genome, (2) the intact viral particle and capsid proteins are required for efficient intracellular delivery of the viral genome, (3) delivery of the viral genome triggers interferon regulatory factor-3 (IRF3) phosphorylation, and (4) IRF3 activation is the required dominant antiviral signaling pathway used by APC, whereas the "primary" involvement of NFB, MAPK or Akt pathways are 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.

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