Abstract
Defensins are peptides that protect the host against microorganisms. Here we show that the θ-defensin retrocyclin 2 (RC2) inhibited influenza virus infection by blocking membrane fusion mediated by the viral hemagglutinin. RC2 was effective even after hemagglutinin attained a fusogenic conformation or had induced membrane hemifusion. RC2, a multivalent lectin, prevented hemagglutinin-mediated fusion by erecting a network of crosslinked and immobilized surface glycoproteins. RC2 also inhibited fusion mediated by Sindbis virus and baculovirus. Human β-defensin 3 and mannan-binding lectin also blocked viral fusion by creating a protective barricade of immobilized surface proteins. This general mechanism might explain the broad-spectrum antiviral activity of many multivalent lectins of the innate immune system.
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Acknowledgements
We thank M. Kozlov, G. Melikyan, B. Podbilewicz, E. Zaitseva and J. Zimmerberg and H. Huang for discussions; and L. Bezrukova for advice on viral titer assay. Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development, and by the National Institutes of Health (RR 20004 to J.A.L. and AI056921 to R.I.L.). The UCLA Functional Proteomics Center was established and equipped by a grant to the University of California at Los Angeles from the W.M. Keck Foundation.
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Supplementary information
Supplementary Fig. 1
RC2 in concentrations up to 200 μg/ml is not toxic for MDCK and HAb2 cells. (PDF 34 kb)
Supplementary Fig. 2
RC2 does not affect membrane contact. (PDF 389 kb)
Supplementary Fig. 3
RC2 inhibits lipid mixing between influenza virus and RBC. (PDF 123 kb)
Supplementary Fig. 4
RC2 inhibits restricted hemifusion. (PDF 38 kb)
Supplementary Fig. 5
RC2 does not alter the pH-dependence of fusion. (PDF 47 kb)
Supplementary Fig. 6
Fusion inhibition by RC2 involves its reversible interactions with cell surface carbohydrates. (PDF 20 kb)
Supplementary Fig. 7
Multivalency of RC2. (PDF 226 kb)
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Leikina, E., Delanoe-Ayari, H., Melikov, K. et al. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat Immunol 6, 995–1001 (2005). https://doi.org/10.1038/ni1248
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DOI: https://doi.org/10.1038/ni1248
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