AUY922 abrogates grass carp reovirus pathogenesis by modulating inflammation and apoptosis

Grass carp reovirus (GCRV) is the primary etiological agent of viral hemorrhagic disease in grass carp ( Ctenopharyngodon idella ) and other cyprinids, causing devastating economic losses in freshwater aquaculture worldwide. The existence of multiple pathogenic genotypes (particularly GCRV-I and GCRV-II) and the lack of broadly effective, virus-specific therapeutics underscore an urgent need for host-directed antiviral strategies. However, whether targeting host chaperone systems can control aquatic viral diseases remains largely unknown. Herein, we evaluated the antiviral efficacy and mechanistic basis of AUY922, a specific inhibitor of heat shock protein 90 (HSP90), against GCRV infection using both in vitro (CIK cells) and in vivo ( Gobiocypris rarus ) models. AUY922 exhibited potent antiviral activity with low cytotoxicity, showing a half-maximal inhibitory concentration (IC 50 ) of 5.96 nM. Prophylactic, therapeutic, and co-incubation treatments all significantly suppressed GCRV-I replication in vitro . In a highly susceptible GCRV-II challenge model, prophylactic administration of AUY922 (10 mg/kg) significantly increased survival rates from 18.18% to 59.09%, reduced tissue viral loads and markedly alleviated systemic hemorrhage as well as histopathological lesions in the gills, kidney, and brain. Mechanistically, AUY922 downregulated the transcription of putative host entry receptors and was accompanied by reduced inflammatory and apoptotic responses during GCRV infection. Collectively, these findings demonstrate that pharmacological inhibition of HSP90 effectively abrogates GCRV pathogenesis, accompanied by reduced expression of viral entry-associated factors, and weaker inflammatory and apoptotic responses. AUY922 therefore represents a promising host-directed antiviral candidate against GCRV and provides proof of concept that targeting host chaperone networks may be a broader strategy for controlling aquatic viral diseases.