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<p>Persistent hyposmia is a hallmark of post COVID-19 conditions, yet the mechanisms sustaining olfactory dysfunction after viral clearance remain poorly understood. Here, using mouse models of SARS-CoV-2 infection, we show that virus-induced senescence-like changes in uninfected olfactory mucosal fibroblasts persist long after viral clearance and drive prolonged olfactory dysfunction. These senescence-like cells secrete SASP factors, including IFNγ, CXCL9, and CXCL11, thereby recruiting γδ T cells to the olfactory mucosa. The accumulated γδ T cells produce excessive IL-17A, which acts on IL-17 receptor A expressed on olfactory sensory neurons, leading to sustained impairment of their function. Genetic ablation of senescence pathways (p16/p21 double knockout), pharmacological elimination of senescent cells with the senolytic drug ABT263, or olfactory neuron-specific deletion of IL-17 receptor A each significantly alleviate prolonged olfactory dysfunction. These findings identify a senescence–γδ T cell–IL-17A axis as a key driver of prolonged hyposmia following SARS-CoV-2 infection in mice.</p>

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Senescence-like cells recruit γδ T cells to drive prolonged hyposmia after SARS-CoV-2 infection in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Shunya Tsuji,
  • Sosuke Nakano,
  • Koyu Ito,
  • Shohei Minami,
  • Ken Uemura,
  • Yusuke Konishi,
  • Masahiro Wakita,
  • Yumiko Okumura,
  • Shimpei Kawamoto,
  • Akari Matsuki,
  • Shinji Nakaoka,
  • Chikako Ono,
  • Hiroo Takahashi,
  • Itsuki Anzai,
  • Tokiko Watanabe,
  • Akiyoshi Uezumi,
  • Yoshiharu Matsuura,
  • Takeshi Kobayashi,
  • Toru Okamoto,
  • Akio Tsuboi,
  • Masataka Asagiri,
  • Eiji Hara

摘要

Persistent hyposmia is a hallmark of post COVID-19 conditions, yet the mechanisms sustaining olfactory dysfunction after viral clearance remain poorly understood. Here, using mouse models of SARS-CoV-2 infection, we show that virus-induced senescence-like changes in uninfected olfactory mucosal fibroblasts persist long after viral clearance and drive prolonged olfactory dysfunction. These senescence-like cells secrete SASP factors, including IFNγ, CXCL9, and CXCL11, thereby recruiting γδ T cells to the olfactory mucosa. The accumulated γδ T cells produce excessive IL-17A, which acts on IL-17 receptor A expressed on olfactory sensory neurons, leading to sustained impairment of their function. Genetic ablation of senescence pathways (p16/p21 double knockout), pharmacological elimination of senescent cells with the senolytic drug ABT263, or olfactory neuron-specific deletion of IL-17 receptor A each significantly alleviate prolonged olfactory dysfunction. These findings identify a senescence–γδ T cell–IL-17A axis as a key driver of prolonged hyposmia following SARS-CoV-2 infection in mice.