人肠道防御素演化 z-bio 2025-02-11 375

　Figure: A research framework based on multi omics for the interaction mechanism and intervention strategy between human gut alpha defense factor 5 (HD5) and Shigella　　

　　Under the support of National Natural Science Foundation of China projects (approval numbers: 32125009, 32070134, 32270188, 82030062, 32222022), Professor Ye Kai's team from Xi'an Jiaotong University, together with Professor Lu Wuyuan's team from Fudan University and Professor Philippe J. Sansonetti's team from Pasteur Institute in France, has made significant progress in the field of human gut defense factor evolution. The research results are titled "Shigella infection is facilitated by interaction of human intestinal alpha defensin 5 with colon epithelial receptor P2Y11" and will be featured on the cover on February 3, 2025. The article was published online in Nature Microbiology. Paper link: https://www.nature.com/articles/s41564-024-01901-9 .

　　Human intestinal alpha defensin 5 (HD5) is an immune factor that only exists in the human gut and has long been considered the "guardian" of gut health, capable of killing various pathogens. However, research has found that HD5 may "assist the tyrant" when facing Shigella, helping the bacteria invade the human body. The mechanism behind this contradictory phenomenon has not been fully explained. The Sino French joint research team led by Professor Ye Kai has revealed the "dual role" mechanism of HD5 through the joint mining of multi omics techniques and multidimensional omics data. Research has found that HD5, in addition to its bactericidal effect, can specifically bind to the P2Y11 receptor on the surface of colon epithelial cells, activate the cAMP PKA signaling pathway, cause host cell cytoskeleton rearrangement, and rapidly form a large number of filamentous pseudopodia structures. These structures were supposed to help repair intestinal damage, but Shigella "hijacked" this process by rapidly invading host cells using filamentous pseudopodia. Unlike traditional pathogens that evade the immune system through genetic mutations, Shigella has evolved a unique immune escape strategy: it uses HD5 induced changes in the cytoskeleton to invade the host in a free riding manner. This strategy even allowed Shigella to abandon traditional adsorption devices during its evolution, demonstrating its highly adaptable ability to the host environment. The research team further validated through various in vitro and in vivo models, including polarized human colon cell monolayers, dynamic intestinal chip models, and animal models, that the P2Y11 antagonist NF157 can significantly reduce the efficiency of HD5 enhanced Shigella invasion.