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A unique sugar-binding site mediates the distinct anti-influenza activity of pig surfactant protein D.

ABSTRACT: Pigs can act as intermediate hosts by which reassorted influenza A virus (IAV) strains can be transmitted to humans and cause pandemic influenza outbreaks. The innate host defense component surfactant protein D (SP-D) interacts with glycans on the hemagglutinin of IAV and contributes to protection against IAV infection in mammals. This study shows that a recombinant trimeric neck lectin fragment derived from porcine SP-D (pSP-D) exhibits profound inhibitory activity against IAV, in contrast to comparable fragments derived from human SP-D. Crystallographic analysis of the pSP-D fragment complexed with a viral sugar component shows that a unique tripeptide loop alters the lectin site conformation of pSP-D. Molecular dynamics simulations highlight the role of this flexible loop, which adopts a more stable conformation upon sugar binding and may facilitate binding to viral glycans through contact with distal portions of the branched mannoside. The combined data demonstrate that porcine-specific structural features of SP-D contribute significantly to its distinct anti-IAV activity. These findings could help explain why pigs serve as important reservoirs for newly emerging pathogenic IAV strains.

SUBMITTER: van Eijk M

PROVIDER: S-EPMC3411006 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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A unique sugar-binding site mediates the distinct anti-influenza activity of pig surfactant protein D.

van Eijk Martin M Rynkiewicz Michael J MJ White Mitchell R MR Hartshorn Kevan L KL Zou Xueqing X Schulten Klaus K Luo Dong D Crouch Erika C EC Cafarella Tanya R TR Head James F JF Haagsman Henk P HP Seaton Barbara A BA

The Journal of biological chemistry 20120608 32

Pigs can act as intermediate hosts by which reassorted influenza A virus (IAV) strains can be transmitted to humans and cause pandemic influenza outbreaks. The innate host defense component surfactant protein D (SP-D) interacts with glycans on the hemagglutinin of IAV and contributes to protection against IAV infection in mammals. This study shows that a recombinant trimeric neck lectin fragment derived from porcine SP-D (pSP-D) exhibits profound inhibitory activity against IAV, in contrast to c ...[more]

PMID: 22685299

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Project description:Influenza viruses represent a serious threat to human health. Although our research group has previously demonstrated the antiviral and anti‑inflammatory activities of eleutheroside B1, a detailed explanation of the mechanism by which it is effective against the influenza virus remains to be elucidated. In the present study, the transcriptomic responses of influenza A virus‑infected lung epithelial cells (A549) treated with eleutheroside B1 were investigated using high‑throughput RNA sequencing, and potential targets were identified using a molecular docking technique, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) assay, and DNA methylation analysis. The transcriptomic data revealed that there are 1,871 differentially expressed genes (DEGs) between the cells infected with the influenza virus strain variant PR8, and the cells infected with PR8 and treated with eleutheroside B1. Among the DEGs, RNA polymerase II subunit A (POLR2A; encoding the largest subunit of RNA polymerase II) and mannosidase α class II member 1 (MAN2A1) were selected from the molecular docking analysis with eleutheroside B1. The docking score of Drosophila melanogaster MAN2A1 (3BVT) was 11.3029, whereas that of POLR2A was 9.0133. The RT‑qPCR results demonstrated that the expression levels of host genes (MAN2A2, POLR2A) and viral genes (PA, PB1, PB2, HA) were downregulated following eleutheroside B1 treatment. Bisulfite‑sequencing PCR was performed to investigate whether eleutheroside B1 was able to modify the DNA methylation of POLR2A, and the results suggested that the average proportion of methylated CpGs (‑222‑72 bp) increased significantly following treatment with eleutheroside B1. Taken together, these findings suggested that eleutheroside B1 may affect N‑glycan biosynthesis, the chemokine signaling pathway, cytokine‑cytokine receptor interaction and, in particular, may target the POLR2A to inhibit the production of influenza virus genes.

Dataset Information

A unique sugar-binding site mediates the distinct anti-influenza activity of pig surfactant protein D.

Publications

A unique sugar-binding site mediates the distinct anti-influenza activity of pig surfactant protein D.

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