P-glycoprotein inhibits the MAPK/NF-KB pathway and activates autophagy and oxidative stress to improve GPS resistance in vivo and in vitro.

Glaesserella parasuis (Gps) is an important pathogen that causes polyserositis, peritonitis and meningitis in pigs, causing considerable economic losses to the pig industry worldwide. In recent years, due to the abuse of antibiotic drugs, Gps drug resistance and multi-drug resistance have become increasingly serious, especially for macrolides. Thus, by inducing Tydigrosin resistant bacteria, we found that PgtP is a Gps-produced virulence gene that plays a crucial role in the disease, but its interaction in host cells remains unclear. To characterize the function of the PgtP gene in Gps, we constructed ΔPgtP mutants. Notably, deletion of the PgtP gene resulted in increased adhesion to mouse macrophages, suggesting that PgtP is essential for adhesion of Gps. In addition, as a member of the cell membrane transporter family, PgtP links activated inflammation with autophagy and oxidative stress metabolism. To further investigate the role of PgtP, we infected mouse macrophages with ΔPgtP mutants and wild strains respectively. We found that ΔPgtP mutations can reduce the level of intracellular reactive oxygen species (ROS), up-regulate the number of intracellular autophagosomes, and down-regulate the expression of cytokines IL-6 and TNF-a. Further mechanistic studies showed that PGTP-associated p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were involved in autophagy and oxidative stress and demonstrated that the related signaling pathways were also activated in mice. These results highlight the potential of PgtP as a target for therapeutic intervention and provide important new insights into how it contributes to the aggressiveness and persistence of Gps.