1 Div. of Biochemistry, Faculty. of Pharm., Keio Univ.2 PRESTO, JST.3 Faculty. of Pharm., Hokkaido Univ.4 Dept. of Immunobiology, Yale Sch. of Med.5 Dept. of Microbiology and Immunology, Sch. of Pharm. Sci., Wakayama Med. Univ.6 Div. of Mucosal Immunology, Res. Center for Systems Immun., Med. Inst. of Bioregulation, Kyushu Univ.Aggravate Secondary Bacterial PneumoniaTh17-Derived RANKL Drives Club-to-M Cell Transdifferentiation to Secondary bacterial pneumonia following influenza virus infection can cause severe disease. While immune cell exhaustion and epithelial damage have been implicated, the precise mechanisms remain unclear. Using a mouse model, we found that susceptibility to Streptococcus pneumoniae infection remained elevated even after recovery from weight loss induced by influenza A virus (PR8 strain) infection. Single-cell RNA sequencing (scRNA-seq) revealed a shift in airway epithelial composition at this late time point, notably with an increase in microfold (M) cells. M cells are specialized epithelial cells typically found in mucosal-associated lymphoid tissues of the intestine, where they initiate mucosal immune responses by transcytosing luminal antigens. In this study, we demonstrate that influenza-induced M cells arise from secretory club cells through RANKL signaling mediated by Th17 cells. Conditional deletion of the RANKL receptor in club cells suppressed M cell induction and reduced mortality associated with secondary bacterial pneumonia. Immunohistochemistry showed that S. pneumoniae enters the tissue via M cells, suggesting that the emergence of M cells in the respiratory tract compromises epithelial barrier integrity post-influenza. These findings highlight how changes in epithelial cell composition following influenza infection can impact susceptibility to subsequent respiratory infections. ○Shunsuke Kimura1,2,3 Shingo Kawai1 Takahiro Yamada1,4 Yutaka Nakamura1,5 Yuki Oya1 Daigo Ito1 Mayumi Endo1 Shinichiro Sawa6 Koji Hase154P 024
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