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<p>Secretory immunoglobulin A (sIgA), the first line of defense against mucosal epithelial infections, is a multimer. Although multimeric sIgA shows higher antiviral activity than monomeric IgA, the mechanism underlying this enhancement and the functional differences among IgA subclasses remain unclear. Here, we generated recombinant monomeric and multimeric IgA1 and IgA2m2 antibodies from clone F045-092, which targets the head domain of influenza A virus (IAV) hemagglutinin (HA) and inhibits viral entry, and compared their functional properties. Monomeric IgA1 inhibited viral entry but not viral release. Multimerization of IgA1 enhanced viral entry inhibition and conferred the additional function of inhibiting viral release. In contrast, monomeric IgA2m2 inhibited both viral entry and release and its multimerization enhanced these inhibitory effects. Importantly, treatment of IAV particles with multimeric sIgA or monomeric IgA2m2 induced viral aggregation via IgA-mediated tethering of neighboring virus particles, as visualized via cryo-electron tomography. Analysis of F(ab′)<sub>2</sub> and Fab fragments from F045-092 IgA2m2 demonstrated that bivalency is essential for antibody-mediated viral aggregation (AVA) by monomeric IgA2m2, further supporting a direct tethering mechanism among virus particles. In conclusion, multimerization of the HA head-targeting IgA tends to enhance the inhibition of viral entry and release through AVA, contributing to its enhanced antiviral activity. Additionally, different IgA subclasses with identical variable regions can exhibit distinct properties in the monomeric form, and subclass switching may confer additional functions. Our findings contribute to the development of virus-aggregating antibodies as a new therapeutic approach that efficiently inhibits viral entry and release at the mucosal epithelium.</p>

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Multimerization of secretory IgA enhances antiviral activity by aggregating influenza A virus particles

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Koji Yamauchi,
  • Yukiko Muramoto,
  • Yoko Fujita-Fujiharu,
  • Ai Hirabayashi,
  • Chiharu Nogami,
  • Tsubasa Ishida,
  • Yukihiko Sugita,
  • Shinji Saito,
  • Kaori Sano,
  • Tadaki Suzuki,
  • Masahiro Nakano,
  • Takeshi Noda

摘要

Secretory immunoglobulin A (sIgA), the first line of defense against mucosal epithelial infections, is a multimer. Although multimeric sIgA shows higher antiviral activity than monomeric IgA, the mechanism underlying this enhancement and the functional differences among IgA subclasses remain unclear. Here, we generated recombinant monomeric and multimeric IgA1 and IgA2m2 antibodies from clone F045-092, which targets the head domain of influenza A virus (IAV) hemagglutinin (HA) and inhibits viral entry, and compared their functional properties. Monomeric IgA1 inhibited viral entry but not viral release. Multimerization of IgA1 enhanced viral entry inhibition and conferred the additional function of inhibiting viral release. In contrast, monomeric IgA2m2 inhibited both viral entry and release and its multimerization enhanced these inhibitory effects. Importantly, treatment of IAV particles with multimeric sIgA or monomeric IgA2m2 induced viral aggregation via IgA-mediated tethering of neighboring virus particles, as visualized via cryo-electron tomography. Analysis of F(ab′)2 and Fab fragments from F045-092 IgA2m2 demonstrated that bivalency is essential for antibody-mediated viral aggregation (AVA) by monomeric IgA2m2, further supporting a direct tethering mechanism among virus particles. In conclusion, multimerization of the HA head-targeting IgA tends to enhance the inhibition of viral entry and release through AVA, contributing to its enhanced antiviral activity. Additionally, different IgA subclasses with identical variable regions can exhibit distinct properties in the monomeric form, and subclass switching may confer additional functions. Our findings contribute to the development of virus-aggregating antibodies as a new therapeutic approach that efficiently inhibits viral entry and release at the mucosal epithelium.