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Interactions of -, β-, and -Defensins with Influenza A Virus and Surfactant Protein D

Mona Doss^*, Mitchell R. White^*, Tesfaldet Tecle^*, Donald Gantz, Erika C. Crouch, Grace Jung, Piotr Ruchala, Alan J. Waring, Robert I. Lehrer and Kevan L. Hartshorn^1,*

^* Department of Medicine, Department of Biophysics, Boston University School of Medicine, Boston, MA 02118; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63104; and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

We have reported that the -defensins human neutrophil peptides (HNP)-1 and HNP-2 neutralize and aggregate influenza A virus (IAV) and promote uptake of IAV by neutrophils. These -defensins were also shown to bind to surfactant protein (SP)-D and reduce its antiviral activity. In this study, we examined retrocyclin (RC)1 and RC2, humanized versions of the antiviral -defensins found in the leukocytes of certain nonhuman primates. RC1 was just as effective as HNP-1–3 in neutralizing IAV, and RC2 and RC101 (an analog of RC1) were more effective. In contrast, human β-defensins (HBDs) showed less neutralizing activity. Human defensins 5 and 6 (mainly produced by intestinal Paneth cells) had viral neutralizing activity similar to HNP-1–3. Like HNP-1–3, RCs induced viral aggregation and promoted the uptake of IAV by neutrophils. We used surface plasmon resonance to evaluate binding of defensins to SP-D. HBDs, HD6, and HNP-4 bound minimally to SP-D. HNP-1–3 and RCs bound SP-D with high affinity; however, unlike HNP-1 and HNP-2, RCs did not inhibit SP-D antiviral activity. HBDs also did not inhibit antiviral activity of SP-D. Given their strong neutralizing activity and compatibility with SP-D, RCs may provide attractive prototypes for designing therapeutics that can prevent or treat respiratory infections caused by IAV.

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 Address correspondence and reprint requests to Dr. Kevan L. Hartshorn, Department of Medicine, Evans Biomedical Research Center Room 414, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118. E-mail address: khartsho{at}bu.edu

² Abbreviations used in this paper: IAV, influenza A virus; RC, retrocyclin; SP, surfactant protein; HNP, human neutrophil peptide; HBD, human β-defensin; BAL, bronchoalveolar lavage; SPR, surface plasmon resonance.