Temperature-dependent IL6-STAT3-HSP90 axis mediates aquatic viral entry

Abstract IL6-STAT3 signaling is a canonical pro-inflammatory pathway that is evolutionarily conserved and plays important roles in both temperature related responses and virus infection. However, our understanding of the molecular mechanisms underpinning the temperature-dependent pathogenesis of aquatic viral diseases remains rudimentary. Here we deploy Grass carp reovirus (GCRV) infection as a model system to explore the temperature dependency of viral seasonality in ectotherms. We discovered that the temperature-dependent activation of IL6-STAT3 signaling was hijacked by GCRV to promote viral entry by increasing the expression of heat shock protein 90 (HSP90). Further biochemical, transcriptomic, and microscopic analyses revealed that major capsid protein VP7 of GCRV interacted with HSP90 and relevant cytoskeleton proteins to enable viral entry. Accordingly, exogenous expression of either IL6, HSP90, or VP7 in cells engendered an increased viral entry in a dose-dependent manner. Interestingly, other viruses infecting invertebrate insects, ectothermic vertebrates (e.g., fish, amphibians), and endothermic mammals (e.g., swine, mouse, human) have evolved a similar mechanism to promote their infection. Altogether, our work delineates a pivotal role of the IL6-STAT3-HSP90 axis in the temperature-dependency of viral entry, pinpointing the feasibility of developing targeted therapies for viral diseases in the future.