Interferon-stimulated gene screening identifies CCND3 as a host restriction factor against emerging high-pathogenic bandaviruses

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a representative high-pathogenic bandavirus (Bandavirus genus, Phenuiviridae family). Inducible expression of interferon-stimulated genes (ISGs) is the foundation of host antiviral defense; however, their roles in bandavirus infection remain elusive. Here, we identify over 200 ISGs potentially inhibiting or promoting bandaviral replication. With SFTSV as the main model, we further systematically uncover the notable antiviral role of one ISG, cyclin D3 (CCND3), against bandaviruses. SFTSV infection induces CCND3 up-regulation and cytoplasmic translocation. CCND3, in turn, inhibits the viral replication in cultured cells and pathogenicity in vivo. The viral nucleoprotein (NP) is the target of CCND3. By its CN domain, CCND3 interacts with NP's "head" region in an RNA-independent manner, suppressing the ribonucleoprotein (RNP) replication machinery activity. Furthermore, consistent with interaction interface mapping and structural modeling analyses, the CCND3-NP interaction blocks NP multimerization, NP-RNA binding, and NP association with viral polymerase, that is, the NP activities essential to RNP construction and functioning. Conversely, the viral nonstructural protein, NSs, can partially antagonize CCND3 by attenuating its induction and promoting autophagic degradation. These findings provide new insights into bandavirus-host interactions and arms race, advancing the understanding of bandavirus infection and probably informing antiviral therapeutic development.