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Multimerization of Surfactant Protein D, but Not Its Collagen Domain, Is Required for Antiviral and Opsonic Activities Related to Influenza Virus¹

Mitchell White^*, Paul Kingma, Tesfaldet Tecle^*, Nilgun Kacak^*, Bruce Linders, John Heuser, Erika Crouch and Kevan Hartshorn^2,*

^* Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Children’s Hospital and Medical Center, Cincinnati, OH 45229; and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Surfactant protein D (SP-D) plays important roles in the initial innate defense against influenza A virus (IAV). The collagen domain of SP-D is probably critical for its homeostatic functions in vivo and has been implicated in the modulation of macrophage responses to SP-D-ligand complexes. For the current studies, we used a panel of rat SP-D mutants lacking all or part of the collagen domain to more specifically evaluate the contributions of this domain to viral interactions. SP-D multimers lacking the collagenous sequence efficiently neutralized Phil82 IAV, promoted neutrophil uptake of IAV, and also potentiated the IAV-induced neutrophil respiratory burst response. A dodecameric mutant with shortened collagenous arms showed enhanced viral aggregation and neuraminidase inhibition, and an increased capacity to inhibit a partially collectin-resistant strain of IAV. By contrast, truncated molecules lacking an N-terminal and collagen domain showed no detectable antiviral and opsonizing activity, despite preservation of lectin activity and detectable viral binding. Thus, multimerization, which is mediated by the N-peptide, is more important than the collagen domain for efficient viral neutralization and opsonization. However, the structure of the collagen domain significantly influences the anti-viral activity of multimerized forms of SP-D.

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 research was supported by National Institutes of Health Grants HL-06931 (to K.L.H.), HD28827 (to P.K.), and HL-44015 and HL-29594 (to E.C.C.).

² Address correspondence and reprint requests to Dr. Kevan L. Hartshorn, Boston University School of Medicine, Evans Biomedical Research Center Building 414, 650 Albany Street, Boston, MA 02118. E-mail address: khartsho{at}bu.edu

³ Abbreviations used in this paper: SP-D, surfactant protein D (recombinant rat SP-D); NCRD, neck and rat SP-D + carbohydrate recognition domain; IAV, influenza A virus; HA, hemagglutinin; NA, neuraminidase.