Inhibition of influenza viral neuraminidase activity by collectins

Boston University, Boston, Massachusetts, United States
Archives of Virology (Impact Factor: 2.39). 02/2007; 152(9):1731-42. DOI: 10.1007/s00705-007-0983-4
Source: PubMed


The collectins, lung surfactant proteins A and D (SP-A and SP-D), contribute to innate host defense against influenza A virus (IAV) in vivo. Although collectins bind to the viral hemagglutinin (HA) and inhibit early stages of viral infection in vitro, they also bind to the neuraminidase (NA) and inhibit NA activity. We used a variety of NA functional assays, viral strains and recombinant (mutant or wild type) collectins to characterize the mechanism of NA inhibition. NA inhibition by SP-D correlates with binding of its carbohydrate recognition domain (CRD) to oligomannose oligosaccharides on the viral hemagglutinin (HA). The effects of SP-D are additive with oseltamivir, consistent with differences in mechanism of action. NA inhibition was observed using fetuin or MDCK cells as a substrate, but not in assays using a soluble sialic acid analogue. Collectin multimerization and CRD binding properties are key determinants for NA inhibition. SP-D had greater NA inhibitory activity than mannose-binding lectin, which in turn had greater activity than SP-A. The markedly greater NA inhibitory activity of SP-D compared to SP-A may partly account for the finding that deletion of the SP-D gene in mice has a greater effect on viral replication in vivo.

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Available from: Mitchell R White, Apr 11, 2014
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    • "MBL has been reported to mediate a range of anti-IAV activities in vitro, including inhibition of virus-induced hemagglutination [85, 86], blocking of NA enzymatic activity [60, 87], opsonization for enhanced neutrophil reactivity to IAV [85, 86], and neutralization of virus infectivity [84, 86–88] (Table 2). These activities are complement-independent and shared by other mammalian collectins such as SP-D and conglutinin. "
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    ABSTRACT: Host defenses against viral infections depend on a complex interplay of innate (nonspecific) and adaptive (specific) components. In the early stages of infection, innate mechanisms represent the main line of host defense, acting to limit the spread of virus in host tissues prior to the induction of the adaptive immune response. Serum and lung fluids contain a range of lectins capable of recognizing and destroying influenza A viruses (IAV). Herein, we review the mechanisms by which soluble endogenous lectins mediate anti-IAV activity, including their role in modulating IAV-induced inflammation and disease and their potential as prophylactic and/or therapeutic treatments during severe IAV-induced disease.
    BioMed Research International 05/2012; 2012:732191. DOI:10.1155/2012/732191 · 2.71 Impact Factor
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    • "It has been shown previously that inhibition of the enzymatic activity of NA successfully inhibited virus replication and viral spread and a class of existing antiviral drugs is based on this principle. To investigate whether IAV NA, which is also glycosylated, can be inhibited by RpSP-D, we used, in contrast to other studies [33], [35], recombinant NA molecules to exclude the interference of the enzymatic activity by binding of RpSP-D to HA. Although the enzymatic activity was inhibited to a certain extent, relatively high RpSP-D doses were required to achieve this. "
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    ABSTRACT: The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs) in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted.
    PLoS ONE 09/2011; 6(9):e25005. DOI:10.1371/journal.pone.0025005 · 3.23 Impact Factor
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    • "NA activity of IAV was measured by an enzyme-linked micro plate assay in which Arachis hypogaea peanut lectin was used to detect β-D-galactose-N-acetylglucosamine sequences exposed after the removal of sialic acid from fetuin [26]. Wells of microtiter plate were coated with 50 μl of fetuin (Sigma F-2379: 20 μl/ml in PBS) overnight at 4°C and washed with PBS. "
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    ABSTRACT: Surfactant protein D (SP-D) plays an important role in innate defense against influenza A viruses (IAVs) and other pathogens. We tested antiviral activities of recombinant human SP-D against a panel of IAV strains that vary in glycosylation sites on their hemagglutinin (HA). For these experiments a recombinant version of human SP-D of the Met11, Ala160 genotype was used after it was characterized biochemically and structurally. Oligosaccharides at amino acid 165 on the HA in the H3N2 subtype and 104 in the H1N1 subtype are absent in collectin-resistant strains developed in vitro and are important for mediating antiviral activity of SP-D; however, other glycans on the HA of these viral subtypes also are involved in inhibition by SP-D. H3N2 strains obtained shortly after introduction into the human population were largely resistant to SP-D, despite having the glycan at 165. H3N2 strains have become steadily more sensitive to SP-D over time in the human population, in association with addition of other glycans to the head region of the HA. In contrast, H1N1 strains were most sensitive in the 1970s-1980s and more recent strains have become less sensitive, despite retaining the glycan at 104. Two H5N1 strains were also resistant to inhibition by SP-D. By comparing sites of glycan attachment on sensitive vs. resistant strains, specific glycan sites on the head domain of the HA are implicated as important for inhibition by SP-D. Molecular modeling of the glycan attachment sites on HA and the carbohydrate recognition domain of SPD are consistent with these observations. Inhibition by SP-D correlates with presence of several glycan attachment sites on the HA. Pandemic and avian strains appear to lack susceptibility to SP-D and this could be a contributory factor to their virulence.
    Respiratory research 10/2008; 9(1):65. DOI:10.1186/1465-9921-9-65 · 3.09 Impact Factor
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