Sialic acid serves as a functional receptor for grass carp reovirus.

Grass carp reovirus (GCRV) causes hemorrhagic disease and substantial economic losses in the aquaculture of grass carp (Ctenopharyngodon idella), a commercially important fish species in China. Although viral entry depends on interactions between viral proteins and host receptors, the specific host molecules mediating this process have not been fully elucidated. Here, we identify cell surface sialic acid (SA) as a critical functional receptor for GCRV. Enzymatic removal of SA markedly impaired viral attachment and infection. Competitive inhibition using SA-binding lectins or soluble SA confirmed that GCRV targets SA moieties on host cells. Genetic knockdown of SA biosynthesis attenuated viral binding and replication, whereas overexpression of SA pathway genes enhanced susceptibility. Surface plasmon resonance demonstrated direct binding between GCRV capsid proteins and soluble SA, and mutational analysis identified key amino acid residues involved. Notably, pretreatment of GCRV with soluble SA significantly improved fish survival and reduced virus-induced immune overactivation in vivo. To assess receptor specificity, parallel experiments using Rana grylio virus (RGV), a phylogenetically unrelated ranavirus, showed that RGV infection was unaffected by SA-targeted interventions, highlighting the specificity of SA utilization by GCRV. Together, these findings identify SA as a functional and specific receptor for GCRV, offering new insights into virus-host interactions and potential antiviral strategies in aquaculture.