Vibrio anguillarum hijacks fish host CypA to activate Ras-MAPK signaling and promote Edwardsiella piscicida entry during co-infection.

Edwardsiella piscicida is a major pathogen in marine aquaculture, and co-infection with Vibrio anguillarum dramatically exacerbates disease severity and mortality. However, the molecular mechanisms by which pathogens cooperatively exploit host factors during co-infection remain elusive. Cyclophilin A (CypA), a key regulator of intercellular communication, is often subverted by pathogens to promote infection. Here, we report that co-infection with E. piscicida and V. anguillarum markedly upregulates and promotes the extracellular secretion of host CypA. Transcriptomic analysis of infected Scophthalmus maximus spleen (SMSP) cells revealed that this CypA upregulation is linked to the modulation of the Ras-MAPK signaling axes. Activation of these pathways leads to actin cytoskeleton remodeling, which in turn facilitates the invasion of E. piscicida. Collectively, these findings demonstrate that V. anguillarum promotes E. piscicida co-infection by hijacking the host's CypA-dependent signaling pathways, leading to actin remodeling. This work identifies CypA as a critical node in polymicrobial synergy and a promising therapeutic target for combating bacterial co-infections in aquaculture.