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<p>As a member of the <i>Betacoronavirus</i> genus, bovine coronavirus (BCoV) is a major etiological agent in cattle, causing diarrhea, fever, and reduced milk production, thereby imposing a substantial economic burden on the livestock industry. However, the molecular mechanisms underlying BCoV pathogenesis remain incompletely defined. In this study, we report that BCoV infection of Madin–Darby bovine kidney (MDBK) cells activates ZBP1–PANoptosome-associated signaling and induces the host sialidase neuraminidase 1 (Neu1). Functional studies using CRISPR–Cas9-mediated knockdown revealed that <i>Neu1</i> depletion attenuated ZBP1–PANoptosome activation and reduced viral replication in vitro. Co-immunoprecipitation and GST pull-down assays, together with molecular docking and molecular dynamics analyses, supported a physical association between Neu1 and ZBP1, suggesting a potentially stable interaction interface. In vivo, oral inoculation of BALB/c mice with BCoV resulted in increased Neu1 and ZBP1 signals with partial colocalization in brain and colonic tissues, accompanied by decreased serum sialic acid levels and elevated interleukin-1 beta (IL-1β), which was consistent with Neu1 activation and enhanced inflammatory responses. Histopathological examination further revealed progressive vascular congestion and epithelial injury, suggesting an association between Neu1–ZBP1 signaling and virus-induced tissue damage. Collectively, our findings suggest that Neu1 may contribute to ZBP1-associated PANoptosis during BCoV infection and link sialic acid metabolism to nucleic acid-sensing and inflammatory cell death responses. These results provide mechanistic insight into BCoV pathogenesis and suggest Neu1 as a potential target for future studies aimed at controlling coronavirus infections in cattle and possibly other species.</p>

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Neu1 inhibition restrains BCoV replication and modulates ZBP1-dependent PANoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Haoyuan Ma,
  • Jiawei Zhao,
  • Kai Yu,
  • Siqi Zhang,
  • Jilong Liu,
  • Hao Yu,
  • Shuoning Cao,
  • Jianyou Jin,
  • Shujiang Xue,
  • Qiang Li,
  • Zhiqiang Xu,
  • Shengwei Ji,
  • Chenghui Li,
  • Xinpeng Ji,
  • Zheng Sun,
  • Jingrui Hao,
  • Jialiang Xie,
  • Rumeng Tian,
  • Xifeng Zhang,
  • Rui Du,
  • Xu Gao

摘要

As a member of the Betacoronavirus genus, bovine coronavirus (BCoV) is a major etiological agent in cattle, causing diarrhea, fever, and reduced milk production, thereby imposing a substantial economic burden on the livestock industry. However, the molecular mechanisms underlying BCoV pathogenesis remain incompletely defined. In this study, we report that BCoV infection of Madin–Darby bovine kidney (MDBK) cells activates ZBP1–PANoptosome-associated signaling and induces the host sialidase neuraminidase 1 (Neu1). Functional studies using CRISPR–Cas9-mediated knockdown revealed that Neu1 depletion attenuated ZBP1–PANoptosome activation and reduced viral replication in vitro. Co-immunoprecipitation and GST pull-down assays, together with molecular docking and molecular dynamics analyses, supported a physical association between Neu1 and ZBP1, suggesting a potentially stable interaction interface. In vivo, oral inoculation of BALB/c mice with BCoV resulted in increased Neu1 and ZBP1 signals with partial colocalization in brain and colonic tissues, accompanied by decreased serum sialic acid levels and elevated interleukin-1 beta (IL-1β), which was consistent with Neu1 activation and enhanced inflammatory responses. Histopathological examination further revealed progressive vascular congestion and epithelial injury, suggesting an association between Neu1–ZBP1 signaling and virus-induced tissue damage. Collectively, our findings suggest that Neu1 may contribute to ZBP1-associated PANoptosis during BCoV infection and link sialic acid metabolism to nucleic acid-sensing and inflammatory cell death responses. These results provide mechanistic insight into BCoV pathogenesis and suggest Neu1 as a potential target for future studies aimed at controlling coronavirus infections in cattle and possibly other species.