Xu Dan, Guo Mengyao, Xu Xin, Luo Gan, Liu Yaxin, Bush Stephen J, Wang Chengyao, Xu Tun, Zeng Wenxin, Liao Chongbing, Wang Qingxia, Zhao Wei, Zhao Wenying, Liu Yuezhuangnan, Li Shanshan, Zhao Shuangshuang, Jiu Yaming, Sauvonnet Nathalie, Lu Wuyuan, Sansonetti Philippe J, Ye Kai
Key Laboratory of Biomedical Information Engineering (MOE), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Science, Fudan University, Shanghai, China.
Nat Microbiol. 2025 Feb;10(2):509-526. doi: 10.1038/s41564-024-01901-9. Epub 2025 Feb 3.
Human enteric α-defensin 5 (HD5) is an immune system peptide that acts as an important antimicrobial factor but is also known to promote pathogen infections by enhancing adhesion of the pathogens. The mechanistic basis of these conflicting functions is unknown. Here we show that HD5 induces abundant filopodial extensions in epithelial cells that capture Shigella, a major human enteroinvasive pathogen that is able to exploit these filopodia for invasion, revealing a mechanism for HD5-augmented bacterial invasion. Using multi-omics screening and in vitro, organoid, dynamic gut-on-chip and in vivo models, we identify the HD5 receptor as P2Y11, a purinergic receptor distributed apically on the luminal surface of the human colonic epithelium. Inhibitor screening identified cAMP-PKA signalling as the main pathway mediating the cytoskeleton-regulating activity of HD5. In illuminating this mechanism of Shigella invasion, our findings raise the possibility of alternative intervention strategies against HD5-augmented infections.
人肠道α-防御素5（HD5）是一种免疫系统肽，作为一种重要的抗菌因子，但也已知通过增强病原体的黏附来促进病原体感染。这些相互矛盾的功能的机制基础尚不清楚。在这里，我们表明HD5在上皮细胞中诱导大量丝状伪足延伸，这些丝状伪足捕获志贺氏菌，志贺氏菌是一种主要的人类肠道侵袭性病原体，能够利用这些丝状伪足进行侵袭，揭示了HD5增强细菌侵袭的机制。使用多组学筛选以及体外、类器官、动态肠道芯片和体内模型，我们确定HD5受体为P2Y11，一种顶端分布于人类结肠上皮腔表面的嘌呤能受体。抑制剂筛选确定cAMP-PKA信号通路是介导HD5细胞骨架调节活性的主要途径。在阐明志贺氏菌侵袭机制的过程中，我们的发现增加了针对HD5增强感染的替代干预策略的可能性。
