The shared immunometabolic responses between dexamethasone-induced hepatobiliary syndrome and GCRV II-caused hemorrhagic disease reveal the pivotal role of autophagy and Hsp90 activity in metabolic and infectious diseases

Abstract

Contamination by dexamethasone (DEX) in aquatic environments is expected to rise significantly as it is used in the treatment of inflammation, allergies, and autoimmune disorders, especially COVID-19. However, the underlying effects and mechanisms of DEX in leading to metabolic or infectious diseases have remained largely unexplored in teleosts. Here, we used zebrafish (Danio rerio) as a model to study the effects of DEX exposure on metabolic and infectious diseases. We found that DEX-induced hepatobiliary syndrome significantly increased susceptibility to type II grass carp reovirus (GCRV-II), which causes severe hemorrhagic disease in aquaculture. Comparative transcriptomic analysis demonstrated the shared and disease-specific immunometabolic responses among zebrafish larvae with hepatobiliary syndrome and/or GCRV-II infection. Moreover, compared with those of wild-type zebrafish, zebrafish larvae with DEX-induced hepatobiliary syndrome and/or GCRV-II infection presented increased expression of inflammatory markers (il1b), coagulation markers (fibrinogens and antithrombin III), and genes involved in autophagy, including hsp90aa. In vivo inhibition of autophagy via 3-MA and Hsp90 activity via geldanamycin markedly suppressed hepatic lipid deposition and reactive oxygen species accumulation caused by hepatobiliary syndrome and/or GCRV-II infection, thus significantly reducing the severity of disease and level of mortality induced by DEX and/or GCRV-II infection. In conclusion, our findings establish that the inhibition of autophagy and Hsp90 activity are promising therapeutic targets for DEX-induced hepatobiliary syndrome, GCRV-II infection, and DEX-induced hepatobiliary syndrome complicated with GCRV-II infection.