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Dengue Virus Induces Expression of CXC Chemokine Ligand 10/IFN--Inducible Protein 10, Which Competitively Inhibits Viral Binding to Cell Surface Heparan Sulfate¹

Jia-Perng Chen^2,*, Hsin-Lin Lu^2,*, Szu-Liang Lai^2,*, Gabriele S. Campanella, Jui-Ming Sung, Mei-Yi Lu, Betty A. Wu-Hsieh, Yi-Ling Lin^*, Thomas E. Lane^¶, Andrew D. Luster and Fang Liao^3,*,

^* Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; and ^¶ Department of Molecular Biology, University of California, Irvine, CA 92679

Dengue virus is an arthropod-borne flavivirus that causes a mild febrile illness, dengue fever, or a potentially fatal syndrome, dengue hemorrhagic fever/dengue shock syndrome. Chemokines primarily orchestrate leukocyte recruitment to the areas of viral infection, which makes them critical mediators of immune and inflammatory responses. In the present study, we investigated the induction and function of chemokines in mice early after infection with dengue virus in vivo. We found that CXCL10/IFN--inducible protein 10 (IP-10) expression was rapidly and transiently induced in liver following infection. The expressed CXCL10/IP-10 likely mediates the recruitment of activated NK cells, given that anti-CXCL10/IP-10-treated mice showed diminished NK cell infiltration and reduced hepatic expression of effector molecules in activated NK cells after dengue virus infection. Of particular interest, we found that CXCL10/IP-10 also was able to inhibit viral binding to target cells in vitro. Further investigation revealed that various CXCL10/IP-10 mutants, in which the residues that mediate the interaction between the chemokine and heparan sulfate were substituted, failed to exert the inhibitory effect on dengue binding, which suggests that CXCL10/IP-10 competes with dengue virus for binding to heparan sulfate on the cell surface. Moreover, subsequent plaque assays showed that this inhibition of dengue binding blocked viral uptake and replication. The inhibitory effect of CXCL10/IP-10 on the binding of dengue virus to cells may represent a novel contribution of this chemokine to the host defense against viral infection.

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 grants from the National Health Research Institutes, National Science Council, and Academia Sinica in Taiwan.

² J.-P.C., H.-L.L., and S.-L.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Fang Liao, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. E-mail address: fl9z{at}ibms.sinica.edu.tw

⁴ Abbreviations used in this paper: DV, dengue virus; MOI, multiplicity of infection; IP-10, IFN--inducible protein 10; GAG, glycosaminoglycan; RPA, RNase protection assay; Mig, monokine induced by IFN-; ADE, Ab-dependent enhancement.

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