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Fleury, Damien; Barrère, B.; Bizebard, Thierry; Daniels, Rod S.; Skehel, J.J.; Knossow, M.

doi:10.1038/9299

Cited by 146 publications

(56 citation statements)

References 28 publications

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“…The dominant form of protective anti-influenza virus immunity is thought to be antibodies against the globular head of HA (30,31). A major mechanism by which such antibodies neutralize influenza virus is steric blocking of the binding of HA to cellular receptors (32)(33)(34). In principle, receptor-binding G147R NAs could enable influenza virus to evade such antibodies by providing an alternative mechanism of cellular attachment.…”

Section: Resultsmentioning

confidence: 99%

Influenza Viruses with Receptor-Binding N1 Neuraminidases Occur Sporadically in Several Lineages and Show No Attenuation in Cell Culture or Mice

Hooper

Crowe

Bloom

2015

J Virol

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In nearly all characterized influenza viruses, hemagglutinin (HA) is the receptor-binding protein while neuraminidase (NA) is a receptor-cleaving protein that aids in viral release. However, in recent years, several groups have described point mutations that confer receptor-binding activity on NA, albeit in laboratory rather than natural settings. One of these mutations, D151G, appears to arise in the NA of recent human H3N2 viruses upon passage in tissue culture. We inadvertently isolated the second of these mutations, G147R, in the NA of the lab-adapted A/WSN/33 (H1N1) strain while we were passaging a heavily engineered virus in the lab. G147R also occurs at low frequencies in the reported sequences of viruses from three different lineages: human 2009 pandemic H1N1 (pdmH1N1), human seasonal H1N1, and chicken H5N1. Here we reconstructed a representative G147R NA from each of these lineages and found that all of the proteins have acquired the ability to bind an unknown cellular receptor while retaining substantial sialidase activity. We then reconstructed a virus with the HA and NA of a reported G147R pdmH1N1 variant and found no attenuation of viral replication in cell culture or change in pathogenesis in mice. Furthermore, the G147R virus had modestly enhanced resistance to neutralization by the Fab of an antibody against the receptor-binding pocket of HA, although it remained completely sensitive to the full-length IgG. Overall, our results suggest that circulating N1 viruses occasionally may acquire the G147R NA receptor-binding mutation without impairment of replicative capacity. IMPORTANCEInfluenza viruses have two main proteins on their surface: one (hemagglutinin) binds incoming viruses to cells, while the other (neuraminidase) helps release newly formed viruses from these same cells. Here we characterize unusual mutant neuraminidases that have acquired the ability to bind to cells. We show that the mutation that allows neuraminidase to bind cells has no apparent adverse effect on viral replication but does make the virus modestly more resistant to a fragment of an antibody that blocks the normal hemagglutinin-mediated mode of viral attachment. Our results suggest that viruses with receptor-binding neuraminidases may occur at low levels in circulating influenza virus lineages.T he surface of an influenza virus contains about 400 trimers of hemagglutinin (HA) and about 100 tetramers of neuraminidase (NA) (1, 2). For decades, the understanding has been that the viral entry and release functions are partitioned neatly between these two proteins. Specifically, HA binds the virus to cell surface sialic acids and then, after the virus is endocytosed, mediates fusion of the viral and host membranes (3-5). NA is a sialidase that cleaves the same cell surface receptors that can be bound by HA, thereby facilitating the release of free virions from host cells and viral aggregates (6). While enzymatic activity of NA likely contributes to the ability of influenza virus to penetrate airway mucins in vivo to re...

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Section: Resultsmentioning

confidence: 99%

Influenza Viruses with Receptor-Binding N1 Neuraminidases Occur Sporadically in Several Lineages and Show No Attenuation in Cell Culture or Mice

Hooper

Crowe

Bloom

2015

J Virol

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“…12A, B, and D, HC45 inhibits the binding of viruses to cells (50,51). The difference in function between F005-126 and HC45 may be caused by the distinct orientation of the Abs toward the binding sites in HAs, as indicated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

Iba

Fujii

Ohshima

et al. 2014

J Virol

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Neutralizing antibodies that target the hemagglutinin of influenza virus either inhibit binding of hemagglutinin to cellular receptors or prevent the low-pH-induced conformational change in hemagglutinin required for membrane fusion. In general, the former type of antibody binds to the globular head formed by HA1 and has narrow strain specificity, while the latter type binds to the stem mainly formed by HA2 and has broad strain specificity. In the present study, we analyzed the epitope and function of a broadly neutralizing human antibody against H3N2 viruses, F005-126. The crystal structure of F005-126 Fab in complex with hemagglutinin revealed that the antibody binds to the globular head, spans a cleft formed by two hemagglutinin monomers in a hemagglutinin trimer, and cross-links them. It recognizes two peptide portions (sites L and R) and a glycan linked to asparagine at residue 285 using three complementarity-determining regions and framework 3 in the heavy chain. Binding of the antibody to sites L (residues 171 to 173, 239, and 240) and R (residues 91, 92, 270 to 273, 284, and 285) is mediated mainly by van der Waals contacts with the main chains of the peptides in these sites and secondarily by hydrogen bonds with a few side chains of conserved sequences in HA1. Furthermore, the glycan recognized by F005-126 is conserved among H3N2 viruses. F005-126 has the ability to prevent low-pH-induced conformational changes in hemagglutinin. The newly identified conserved epitope, including the glycan, should be immunogenic in humans and may induce production of broadly neutralizing antibodies against H3 viruses. IMPORTANCEAntibodies play an important role in protection against influenza virus, and hemagglutinin is the major target for virus neutralizing antibodies. It has long been believed that all effective neutralizing antibodies bind to the surrounding regions of the sialic acid-binding pocket and inhibit the binding of hemagglutinin to the cellular receptor. Since mutations are readily introduced into such epitopes, this type of antibody shows narrow strain specificity. Recently, however, broadly neutralizing antibodies have been isolated. Most of these bind either to conserved sites in the stem region or to the sialic acid-binding pocket itself. In the present study, we identified a new neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against H3N2. This epitope may be useful for design of vaccines.

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“…The Rutgers PDB data base was searched using the Protein BLAST search option (www.ncbi.nlm.nih.gov/BLAST) to select known structures that are related to the D3 or D4 domain. The variable domain of the light chain of anti-P24 (human immunodeficiency virus-1) Fab fragment CB41 (PDB code 1CFT) (52) was selected for modeling the D3 domain of pIgR; the D4 domain was modeled using the variable domain of the light chain of the antibody against influenza virus hemagglutinin (PDB code 1QFU) (53). They share ϳ20% sequence identity with the D3 and D4 domains of pIgR, respectively.…”

Section: Methodsmentioning

confidence: 99%

The Human Polymeric Immunoglobulin Receptor Binds to Streptococcus pneumoniae via Domains 3 and 4

Lamm

et al. 2003

Journal of Biological Chemistry

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Streptococcus pneumoniae (the pneumococcus) is a major cause of bacterial pneumonia, middle ear infection (otitis media), sepsis, and meningitis. Our previous study demonstrated that the choline-binding protein A (CbpA) of S. pneumoniae binds to the human polymeric immunoglobulin receptor (pIgR) and enhances pneumococcal adhesion to and invasion of cultured epithelial cells. In this study, we sought to determine the CbpAbinding motif on pIgR by deletional analysis. The extracellular portion of pIgR consists of five Ig-like domains (D1-D5), each of which contains 104 -114 amino acids and two disulfide bonds. Deletional analysis of human pIgR revealed that the lack of either D3 or D4 resulted in the loss of CbpA binding, whereas complete deletions of domains D1, D2, and D5 had undetectable impacts. Subsequent analysis showed that domains D3 and D4 together were necessary and sufficient for the ligandbinding activity. Furthermore, CbpA binding of pIgR did not appear to require Ca 2؉ or Mg 2؉ . Finally, treating pIgR with a reducing agent abolished CbpA binding, suggesting that disulfide bonding is required for the formation of CbpA-binding motif(s). These results strongly suggest a conformational CbpA-binding motif(s) in the D3/D4 region of human pIgR, which is functionally separated from the IgA-binding site(s).

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Untitled

Cited by 146 publications

References 28 publications

Influenza Viruses with Receptor-Binding N1 Neuraminidases Occur Sporadically in Several Lineages and Show No Attenuation in Cell Culture or Mice

Influenza Viruses with Receptor-Binding N1 Neuraminidases Occur Sporadically in Several Lineages and Show No Attenuation in Cell Culture or Mice

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

The Human Polymeric Immunoglobulin Receptor Binds to Streptococcus pneumoniae via Domains 3 and 4

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