Aeromonas hydrophila causes ferroptotic damage via its secreted effectors targeting splenic macrophages in teleost

Abstract

Aeromonas hydrophila (A. hydrophila) is a well-known pathogen leading to huge economic losses in aquaculture. Using grass carp, a commercially important fish species, as a model, we found that A. hydrophila decreased fish survival, caused ferrugination and induced lipid peroxidation damage especially in spleen. Further investigations revealed that the bacteria particularly utilized secretory effectors to trigger ferroptosis by specially targeting splenic macrophages in which A. hydrophila effectors significantly elevated intracellular Fe2+ levels, initiated lipid peroxidation, and dampened mitochondrial membrane potential. Mechanistically, bacterial effectors could degrade ferritin and ferroportin1 via autophagy and proteasome pathways respectively, leading intracellular iron accumulation. Moreover, the effectors promoted glutathione (GSH) depletion via their stimulatory effects on ROS generation in splenic macrophages, suggesting that A. hydrophila effectors might suppress GSH-dependent cellular antioxidant system. Finally, an in vivo study uncovered that ferroptosis inhibitors significantly improve fish survival, ameliorated oxidative damage, and reduced bacterial load in spleen. Our data highlight the ferroptotic damage of A. hydrophila via its effectors in teleost and suggest ferroptosis is a potential target for fish against A. hydrophila infection.