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Lectin-mediated binding and sialoglycans of porcine surfactant protein D synergistically neutralize influenza A virus

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  • Lectin-mediated binding and sialoglycans of porcine surfactant protein D synergistically neutralize influenza A virus

    J Biol Chem. 2018 May 16. pii: jbc.RA117.001430. doi: 10.1074/jbc.RA117.001430. [Epub ahead of print]
    Lectin-mediated binding and sialoglycans of porcine surfactant protein D synergistically neutralize influenza A virus.

    van Eijk M1, Rynkiewicz MJ2, Khatri K3, Leymarie N4, Zaia J2, White MR4, Hartshorn KL4, Cafarella TR2, Van Die I5, Hessing M6, Seaton BA7, Haagsman HP8.
    Author information

    Abstract

    Innate immunity is critical in the early containment of influenza A virus (IAV) infection, and surfactant protein D (SP-D) plays a crucial role in the pulmonary defense against IAV. In pigs, which are important intermediate hosts during the generation of pandemic IAVs, SP-D uses its unique carbohydrate recognition domain (CRD) to interact with IAV. An N-linked CRD-glycosylation provides interactions with the sialic acid binding site of IAV, and a tripeptide loop at the lectin binding site facilitates enhanced interactions with IAV glycans. Here, to investigate both mechanisms of IAV neutralization in greater detail, we produced an N-glycosylated neckCRD fragment of porcine SP-D (RpNCRD) in HEK293 cells. X-ray crystallography disclosed that the N-glycan did not alter the CRD backbone structure including the lectin site conformation, but revealed a potential second non-lectin binding site for glycans. IAV hemagglutination inhibition, IAV aggregation and neutralization of IAV infection studies showed that RpNCRD, unlike the human analogue RhNCRD, exhibits potent neutralizing activity against pandemic A/Aichi/68 (H3N2), enabled by both porcine-specific structural features of its CRD. MS analysis revealed an N-glycan site-occupancy of >98% at Asn303 of RpNCRD with complex-type, heterogeneously branched and predominantly α(2,3) sialylated oligosaccharides. Glycan binding array data characterized both RpNCRD and RhNCRD as mannose-type lectins. RpNCRD also bound LewisY structures whereas RhNCRD bound polylactosamine-containing glycans. Presence of the N-glycan in the CRD increases the glycan binding specificity of RpNCRD. These insights increase our understanding of porcine-specific innate defense against pandemic IAV and may inform the design of recombinant SP-D-based antiviral drugs.


    KEYWORDS:

    N-linked glycosylation; antiviral agent; collectin; drug design; host-pathogen interaction; influenza virus; innate immunity; porcine immunology; pulmonary defense; recombinant protein; sialic acid; structural biology; surfactant protein D; viral immunology

    PMID: 29769321 DOI: 10.1074/jbc.RA117.001430
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