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J. Virol. doi:10.1128/JVI.02484-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of Dendritic Cells in antibody dependent enhancement of dengue infection

Department of Retrovirology, Walter Reed Army Institute of Research and Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD 20850; Viral Disease Department, Naval Medical Research Center, Silver Spring, MD 20889; Department of Virus Diseases, Walter Reed Army Institute of Research, Silver Spring, MD 20889; Department of Internal Medicine, Hasan Sadikin Hospital, Bandung, Indonesia, National Institute of Health Research and Development, Indonesian Ministry of Health, Jakarta, Indonesia, Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok-noi, Bangkok 10700, Thailand, Uniformed Services University of the Health Sciences, Department of Medicine, Bethesda, MD 20814

^* To whom correspondence should be addressed. Email: mmarovich{at}hivresearch.org.

	Abstract

Dengue viruses (DV), composed of 4 distinct serotypes (DV1-4), cause 50-100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of Dendritic Cell-Specific Intercellular adhesion molecule-3 Grabbing Nonintegrin (DC-SIGN) and requires FcRIIa. Mature DC exhibited ADE whereas immature DC, expressing higher levels of DC-SIGN and similar FcRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo dengue protein synthesis, increased viral RNA production and release, and increased infectivity of the supernatants in mature DC. Interestingly, TNF- and IL-6, but not IL-10 or IFN-, were released in the presence of dengue sera but generally only at enhancement titers suggesting a signaling component of ADE. FcRIIa inhibition with monoclonal antibodies abrogated antibody dependent enhancement and associated downstream consequences. DV versatility in entry routes (FcRIIa or DC-SIGN) in mature DC broadens target options and suggests additional ways for DC to contribute to the pathogenesis of severe dengue infection. Studying the cellular targets of DV infection and their susceptibility to ADE will aid our understanding of complex disease and contribute to the field of vaccine development.