Timing and magnitude of the type-I interferon response are determinants of disease tolerance in arbovirus infection

Infected hosts possess two alternative strategies to protect themselves against the negative impact of virus infections: (i) "resistance", directed to abrogate virus replication, or (ii) "disease tolerance", aimed to avoid organ and tissue damage without overly controlling viral burden. The overall principles governing pathogen resistance are well understood, while less is known about those involved in disease tolerance. Here, we studied bluetongue virus (BTV), the cause of a major disease of ruminants, bluetongue, as a model system to investigate the mechanisms of disease tolerance. BTV induces clinical disease mainly in sheep, while cattle are considered reservoirs of infection, rarely exhibiting clinical symptoms despite sustained viremia. Here, we show that BTV consistently reaches higher titres in ovine primary cells, compared to cells derived from cattle. The variable replication kinetics of BTV in sheep and cattle cells were mostly abolished by abrogating the cell type-I interferon (IFN) response. By screening a library of bovine interferon stimulated genes (ISGs), we identified restriction factors blocking BTV replication, however both sheep and cattle orthologues of these antiviral genes possess anti-BTV properties. Importantly, we demonstrate that BTV induces a faster host cell protein synthesis shutoff in primary sheep cells, compared to cattle cells, which results in an earlier downregulation of antiviral proteins. Moreover, by RNAseq we also show a more pronounced expression of ISGs in BTV infected cattle cells compared to sheep cells. Our data provide a new perspective on how the type-I IFN response in reservoir species can have overall positive effects on both virus and host evolution.