Viral-Induced Heme Accumulation Subverts TLR4bb-Mediated Antiviral Immunity by Triggering Gut Microbiota Dysbiosis, Metabolic Dysregulation, and Ferroptosis

This study identifies grass carp TLR4bb as a crucial hub coordinating antiviral immunity with heme metabolism, redox balance, and gut microbiota during GCRV-II infection. While TLR4bb recruits TIRAP/MyD88/TRIF to activate IFN signaling against the virus, its synergy with heme and viral sensing triggers mitochondrial ROS and inflammatory cell death. Notably, GCRV-II–induced heme accumulation progressively compromises TLR4bb's protective role, driving mitochondrial dysfunction and ferroptosis. In vivo, tlr4bb silencing increases susceptibility to infection and shifts the intestinal environment toward redox imbalance and microbial dysbiosis, highlighting the delicate balance between TLR4bb-mediated defense and metabolic homeostasis.