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

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

Department of Molecular Biology, Research Institute for Microbial Diseases, The University of Osaka, Suita, Japan. [email protected]. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that senescence-like cells in the olfactory mucosa recruit γδ T cells, leading to prolonged hyposmia after SARS-CoV-2 infection. This research is relevant as it explores the mechanisms of cellular senescence and its implications for prolonged dysfunction, which are central to understanding aging processes and age-related diseases.

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