Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

Nikolaos M. Nikolaidis, Mitchell R. White, Kimberly Allen, Shweta Tripathi, Li Qi, Barbara McDonald, Jeffery Taubenberger, Barbara A. Seaton, Francis X. McCormack, Erika C. Crouch, Kevan L. Hartshorn

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

We recently reported that a trimeric neck and carbohydrate recognition domain (NCRD) fragment of human surfactant protein D (SP-D), a host defense lectin, with combinatorial substitutions at the 325 and 343 positions (D325A+R343V) exhibits markedly increased antiviral activity for seasonal strains of influenza A virus (IAV). The NCRD binds to glycan-rich viral envelope proteins including hemagglutinin (HA). We now show that replacement of D325 with serine to create D325S+R343V provided equal or increased neutralizing activity compared with D325A+R343V. The activity of the double mutants was significantly greater than that of either single mutant (D325A/S or R343V). D325A+R343V and D325S+R343V also strongly inhibited HA activity, and markedly aggregated, the 1968 pandemic H3N2 strain, Aichi68. D325S+R343V significantly reduced viral loads and mortality of mice infected with Aichi68, whereas wild-type SP-D NCRD did not. The pandemic H1N1 strains of 1918 and 2009 have only one N-linked glycan side on the head region of the HA and are fully resistant to inhibition by native SP-D. Importantly, we now show that D325A+R343V and D325S+R343V inhibited Cal09 H1N1 and related strains, and reduced uptake of Cal09 by epithelial cells. Inhibition of Cal09 was mediated by the lectin activity of the NCRDs. All known human pandemic strains have at least one glycan attachment on the top or side of the HA head, and our results indicate that they may be susceptible to inhibition by modified host defense lectins.

Original languageEnglish
Pages (from-to)L1036-L1044
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume306
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Collectin
  • Innate immunity
  • Mouse

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