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* Department of Immunology and Molecular Pathology, University College London, Windeyer Institute of Medical Sciences, London, United Kingdom; and
Department of Biochemistry, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104
Innate immune recognition is an important early event in the host response to herpes simplex virus-1 (HSV-1) infection. Dendritic cells (DC) play an important sentinel role in this recognition. Previous studies have shown that monocyte-derived DC (MDDC) respond to HSV-1 by up-regulation of costimulatory molecules and type I IFN release, but the molecular targets on the virus recognized by the DC have not been defined. In this study we show that MDDC recognize and respond to the four essential viral glycoproteins, gB, gD, and gHgL, independent of other viral proteins or nucleic acids. DC recognition of these four glycoproteins leads to the up-regulation of CD40, CD83, CD86, and HLA-DR and to the production of IFN-
and IL-10, but not IL-12p70. Glutaraldehyde-fixation and nonfunctional gH mutants were used to show that recognition of glycoproteins does not require membrane fusion. The nature of the recognition event was probed further by transfecting glycoproteins individually or in combination, by blocking individual proteins with Abs, or by using mutant gD constructs unable to bind to their known cognate receptors. Unexpectedly, MDDC responses were found to require expression of all four glycoproteins. Furthermore, gD mutants that cannot bind nectin-1 and/or herpesvirus entry mediator can still induce DC maturation. Finally, although HSV-1 can signal via the TLR2 receptor, this receptor does not mediate recognition of glycoproteins. Thus, the complex of the four essential HSV-1 entry glycoproteins on the cell surface can provide a target for innate immune recognition of this virus.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Barclay Family Cancer Research Foundation and by the Lewis Foundation. C.K. is supported by Public Health Service Grant AI-0733 84 from the National Institute of Allergy and Infectious Diseases.
2 Address correspondence and reprint requests to Dr. Benjamin M. Chain, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, U.K. E-mail address: b.chain{at}ucl.ac.uk
3 Abbreviations used in this paper: HSV-1, herpes simplex virus-1; DC, dendritic cell; FSC/SSC, forward/side scatter; HVEM, herpesvirus entry mediator; MDDC, monocyte-derived DC; MDLC, monocyte-derived Langerhans cell; MFI, mean fluorescence intensity; MOI, multiplicity of infection; PAMP/PRR, pathogen-associated molecular pattern/pattern recognition receptor; pDC, plasmacytoid DC; RT, room temperature.
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