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CD40 Ligand Enhances Dengue Viral Infection of Dendritic Cells: A Possible Mechanism for T Cell-Mediated Immunopathology^1,2

Peifang Sun^*,¶, Christina M. Celluzzi, Mary Marovich^,¶, Hemavathy Subramanian^*,¶, Michael Eller^¶, Susana Widjaja, Dupeh Palmer, Kevin Porter^*,¶, Wellington Sun and Timothy Burgess^3,*,,¶

^* Naval Medical Research Center, Silver Spring, MD 20910; Naval Medical Research Unit 2, Jakarta, Indonesia; Walter Reed Army Institute of Research, Silver Spring, MD 20910; University of Maryland School of Medicine, Baltimore, MD 21201; and ^¶ Henry M. Jackson Foundation, Rockville, MD 20852

We have previously shown that dengue virus (DV) productively infects immature human dendritic cells (DCs) through binding to cell surface DC-specific ICAM-3-grabbing nonintegrin molecules. Infected DCs are apoptotic, refractory to TNF- stimulation, inhibited from undergoing maturation, and unable to stimulate T cells. In this study, we show that maturation of infected DCs could be restored by a strong stimulus, CD40L. Addition of CD40L significantly reduced apoptosis of DCs, promoted IL-12 production, and greatly elevated the IFN- response of T cells, but yet did not restore T cell proliferation in MLR. Increased viral infection of DCs was also observed; however, increased infection did not appear to be mediated by DC-specific ICAM-3-grabbing nonintegrin, but rather was regulated by decreased production of IFN- and decreased apoptotic death of infected DCs. Because CD40L is highly expressed on activated memory (but not naive) T cells, the observation that CD40L signaling results in enhanced DV infection of DC suggests a possible T cell-dependent mechanism for the immune-mediated enhancement of disease severity associated with some secondary dengue infections.

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 U.S. Navy Work Unit Number 61102A.870.S.A0015 and by U.S. Army Work Unit DAMD17-02-0005.

² The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. government.

³ Address correspondence and reprint requests to Dr. Timothy Burgess, Naval Medical Research Unit 2, FPO AP 96520-8132. E-mail address: burgess{at}namru2.org

⁴ Abbreviations used in this paper: DV, dengue virus; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; DC, dendritic cell; MV, measles virus; rh, recombinant human; MOI, multiplicity of infection; PI, propidium iodide; CBA, cytometric bead array; MFI, mean fluorescence intensity; ADE, Ab-dependent enhancement; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin.