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Background The molecular mechanisms by which probiotics counteract Streptococcus anginosus (S. anginosus) pathogenesis remain poorly understood. Our preliminary work identified Lactiplantibacillus plantarum LPF-01 as a potent antagonist against S. anginosus.Methods This study investigates the molecular crosstalk between LPF-01 and S. anginosus using genetic engineering, protein-protein interaction assays, and gastric organoid models. We specifically focused on the interaction between the probiotic outer membrane protein (OMP) Lp_0927 and the S. anginosus effector TMPC.Results We demonstrated that Lp_0927 from LPF-01 directly binds to the S. anginosus outer membrane protein TMPC. This binding competitively inhibits the interaction between TMPC and the host receptor ANXA2. Consequently, LPF-01 intervention effectively suppressed the S. anginosus-induced expression of pro-inflammatory chemokines Ccl20 and Ccl8. Mechanistically, this antagonism led to the inactivation of the MAPK signaling pathway in gastric epithelial cells.Conclusions LPF-01 exerts its protective role through a specific OMP-decoy mechanism, blocking S. anginosus-host cell interaction and dampening inflammatory cascades. These findings provide a theoretical foundation for using LPF-01 as a targeted therapeutic agent against S. anginosus-related gastric diseases.