Stiftung Tierärztliche Hochschule Hannover (TiHo)

Enhanced antiviral activity of human surfactant protein D by site-specific engineering of the carbohydrate recognition domain

van Eijk, Martin; Hillaire, Marine L. B.; Rimmelzwaan, Guus F. GND; Rynkiewicz, Michael J.; White, Mitchell R.; Hartshorn, Kevan L.; Hessing, Martin; Koolmees, Peter A.; Tersteeg, Monique H.; van Es, Maarten H.; Meijerhof, Tjarko; Huckriede, Anke; Haagsman, Henk P.

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 innate defense against IAV in the lungs. Multivalent lectin-mediated interactions of SP-D with IAVs result in viral aggregation, reduced epithelial infection, and enhanced IAV clearance by phagocytic cells. Previous studies showed that porcine SP-D (pSP-D) exhibits distinct antiviral activity against IAV as compared to human SP-D (hSP-D), mainly due to key residues in the lectin domain of pSP-D that contribute to its profound neutralizing activity. These observations provided the basis for the design of a full-length recombinant mutant form of hSP-D, designated as "improved SP-D" (iSP-D). Inspired by pSP-D, the lectin domain of iSP-D has 5 amino acids replaced (Asp324Asn, Asp330Asn, Val251Glu, Lys287Gln, Glu289Lys) and 3 amino acids inserted (326Gly-Ser-Ser). Characterization of iSP-D revealed no major differences in protein assembly and saccharide binding selectivity as compared to hSP-D. However, hemagglutination inhibition measurements showed that iSP-D expressed strongly enhanced activity compared to hSP-D against 31 different IAV strains tested, including (pandemic) IAVs that were resistant for neutralization by hSP-D. Furthermore, iSP-D showed increased viral aggregation and enhanced protection of MDCK cells against infection by IAV. Importantly, prophylactic or therapeutic application of iSP-D decreased weight loss and reduced viral lung titers in a murine model of IAV infection using a clinical isolate of H1N1pdm09 virus. These studies demonstrate the potential of iSP-D as a novel human-based antiviral inhalation drug that may provide immediate protection against or recovery from respiratory (pandemic) IAV infections in humans.

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van Eijk, M., Hillaire, M.L.B., Rimmelzwaan, G.F., Rynkiewicz, M.J., White, M.R., Hartshorn, K.L., Hessing, M., Koolmees, P.A., Tersteeg, M.H., van Es, M.H., Meijerhof, T., Huckriede, A., Haagsman, H.P., 2019. Enhanced antiviral activity of human surfactant protein D by site-specific engineering of the carbohydrate recognition domain. Frontiers in immunology 10: 2476. https://doi.org/10.3389/fimmu.2019.02476
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