IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody

Shinji Saito, Kaori Sano, Tadaki Suzuki, Akira Ainai, Yuki Taga, Tomonori Ueno, Koshiro Tabata, Kumpei Saito, Yuji Wada, Yuki Ohara, Haruko Takeyama, Takato Odagiri, Tsutomu Kageyama, Kiyoko Ogawa-Goto, Pretty Multihartina, Vivi Setiawaty, Krisna Nur Andriana Pangesti, Hideki Hasegawa

    Research output: Contribution to journalArticle

    Abstract

    Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.

    Original languageEnglish
    Pages (from-to)e1007427
    JournalPLoS Pathogens
    Volume15
    Issue number1
    DOIs
    Publication statusPublished - 2019 Jan 1

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    Secretory Immunoglobulin A
    Neutralizing Antibodies
    Orthomyxoviridae
    Immunoglobulin A
    Antibodies
    Polymerization
    Anti-Idiotypic Antibodies
    Respiratory Mucosa
    Human Influenza
    Mucous Membrane
    Influenza A virus
    Virus Diseases
    Antiviral Agents
    Immunoglobulins
    Vaccines
    Immunoglobulin G

    ASJC Scopus subject areas

    • Parasitology
    • Microbiology
    • Immunology
    • Molecular Biology
    • Genetics
    • Virology

    Cite this

    IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody. / Saito, Shinji; Sano, Kaori; Suzuki, Tadaki; Ainai, Akira; Taga, Yuki; Ueno, Tomonori; Tabata, Koshiro; Saito, Kumpei; Wada, Yuji; Ohara, Yuki; Takeyama, Haruko; Odagiri, Takato; Kageyama, Tsutomu; Ogawa-Goto, Kiyoko; Multihartina, Pretty; Setiawaty, Vivi; Pangesti, Krisna Nur Andriana; Hasegawa, Hideki.

    In: PLoS Pathogens, Vol. 15, No. 1, 01.01.2019, p. e1007427.

    Research output: Contribution to journalArticle

    Saito, S, Sano, K, Suzuki, T, Ainai, A, Taga, Y, Ueno, T, Tabata, K, Saito, K, Wada, Y, Ohara, Y, Takeyama, H, Odagiri, T, Kageyama, T, Ogawa-Goto, K, Multihartina, P, Setiawaty, V, Pangesti, KNA & Hasegawa, H 2019, 'IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody' PLoS Pathogens, vol. 15, no. 1, pp. e1007427. https://doi.org/10.1371/journal.ppat.1007427
    Saito, Shinji ; Sano, Kaori ; Suzuki, Tadaki ; Ainai, Akira ; Taga, Yuki ; Ueno, Tomonori ; Tabata, Koshiro ; Saito, Kumpei ; Wada, Yuji ; Ohara, Yuki ; Takeyama, Haruko ; Odagiri, Takato ; Kageyama, Tsutomu ; Ogawa-Goto, Kiyoko ; Multihartina, Pretty ; Setiawaty, Vivi ; Pangesti, Krisna Nur Andriana ; Hasegawa, Hideki. / IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody. In: PLoS Pathogens. 2019 ; Vol. 15, No. 1. pp. e1007427.
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    abstract = "Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.",
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    AU - Sano, Kaori

    AU - Suzuki, Tadaki

    AU - Ainai, Akira

    AU - Taga, Yuki

    AU - Ueno, Tomonori

    AU - Tabata, Koshiro

    AU - Saito, Kumpei

    AU - Wada, Yuji

    AU - Ohara, Yuki

    AU - Takeyama, Haruko

    AU - Odagiri, Takato

    AU - Kageyama, Tsutomu

    AU - Ogawa-Goto, Kiyoko

    AU - Multihartina, Pretty

    AU - Setiawaty, Vivi

    AU - Pangesti, Krisna Nur Andriana

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