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* Shraga Segal Department of Microbiology and Immunology and National Institute for Biotechnology in the Negev, Ben Gurion University of the Negev, Beer Sheva, Israel;
Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, Paris, France;
Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3012 and Unit of Molecular Prevention and Therapy of Human Diseases, Paris, France;
HKU-Pasteur Research Center, Hong Kong SAR, China; and
¶ Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111
Dengue virus (DV) and West Nile virus (WNV) have become a global concern due to their widespread distribution and their ability to cause a variety of human diseases. Antiviral immune defenses involve NK cells. In the present study, we investigated the interaction between NK cells and these two flaviviruses. We show that the NK-activating receptor NKp44 is involved in virally mediated NK activation through direct interaction with the flavivirus envelope protein. Recombinant NKp44 directly binds to purified DV and WNV envelope proteins and specifically to domain III of WNV envelope protein; it also binds to WNV virus-like particles. These WNV-virus-like particles and WNV-domain III of WNV envelope protein directly bind NK cells expressing high levels of NKp44. Functionally, interaction of NK cells with infective and inactivated WNV results in NKp44-mediated NK degranulation. Finally, WNV infection of cells results in increased binding of rNKp44 that is specifically inhibited by anti-WNV serum. WNV-infected target cells induce IFN-
secretion and augmented lysis by NKp44-expressing primary NK cells that are blocked by anti-NKp44 Abs. Our findings show that triggering of NK cells by flavivirus is mediated by interaction of NKp44 with the flavivirus envelope protein.
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 a grant from the European Commission (INCO-DEV, Contract DENFRAME N 51711) and by the United States-Israel Binational Science Foundation (KSC and AP).
2 O.H., B.R., and L.A.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Angel Porgador, Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. E-mail address: angel{at}bgu.ac.il
4 Abbreviations used in this paper: DV, dengue virus; CHO, Chinese hamster ovary; E, envelope; HA, hemagglutinin; hIgG, human IgG; HMAF, hyperimmune mouse ascites fluid; IV, influenza virus; KVI, Kimron Veterinary Institute; MCS, multiple cloning site; MFI, mean fluorescence intensity; MOI, multiplicity of infection; NCR, natural cytotoxicity receptor; NKp44D, NKp44 extracellular domain; NKp44LP, NKp44 linker peptide; PBST, PBS with 0.05% Tween 20; pNPP, para-nitrophenyl phosphate; S2, Schneider 2; sE, soluble E; Tet, tetracycline; VLP, virus-like particle; WN, West Nile; WNV, WN virus; PhoA, alkaline phosphatase.
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