Interactions of viral proteins from pathogenic and low or non-pathogenic orthohantaviruses with human type I interferon signaling

Rodent-borne orthohantaviruses are asymptomatic in their natural reservoir, but can cause severe diseases in humans. Although an exacerbated immune response relates to hantaviral pathologies, orthohantaviruses have to antagonize the antiviral interferon (IFN) response to successfully propagate in infected cells. We studied here interactions of structural and non-structural (NSs) proteins of pathogenic Puumala (PUUV) and low- or non-pathogenic Tula (TULV) and Prospect Hill (PHV) viruses, with the human IFN pathway. The NSs of all three viruses inhibited RIG-I activated IFN promoter, while only the glycoprotein precursor (GPC) of PUUV, or its cleavage product Gn/Gc, and the nucleocapsid (N) of TULV inhibited it. Moreover, both GPC of PUUV and TULV impacted the IFN stimulated responsive elements (ISRE) promoter. Different viral proteins could thus contribute to inhibition of IFN response in a viral context. While using wild type and variant PUUV and TULV strains encoding truncated NSs proteins showed little effect on viral replication, only PUUV with wild type NSs led to late IFN expression and activation of interferon stimulated genes. This together with identification of particular domains of NSs and different biological processes associated to cellular proteins in complex with NSs, suggested that activation of IFN-I is probably not the only antiviral pathway to be counteracted by orthohantaviruses and that NSs could have multiple functions.