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

Abstract

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.

A Machine Learning Framework to Identify the Correlates of Disease Severity in Acute Arbovirus Infection

“…We conclude that more virulent BTV strains appear to be efficient at modulating the type-I IFN response, allowing the virus to reach higher viral loads and further dissemination to target organs. These data are consistent with our recent findings in BTV infected primary bovine cells 52 .…”

“…Cows are known reservoirs of BTV infection but rarely show clinical disease. Comparison of a virulent strain of BTV in ovine and bovine cells identified the type-I IFN response to be initiated earlier in bovine cells leading to a greater restriction in virus replication 52 . BTV modulates the interferon response through the expression of non-structural proteins with immunomodulatory functions, such as NS3 and NS4, and by inducing host cell translational shutdown [53][54][55][56][57] .…”

“…CPT-Tert cells 71 derive from sheep choroid plexus cells immortalized with simian virus 40 (SV40) T antigen and human telomerase reverse transcriptase, and were propagated in Iscove's modified Dulbecco's medium (IMDM) supplemented with 10% FBS. Immortalised primary ovine endothelial cells were used as described previously 52 . For the RNAseq experiments described below, immortalised ovine endothelial cells were infected in 12-well plates at MOI~10 with either BTV-1IT2006, BTV-1IT2013 or BTV-8FR2017 by spinoculation at 500 x g at 4°C for 1 h.…”

“…After incubation, monolayers were washed with warm PBS to remove any cellular debris and immediately lysed in 750 μL of Trizol. Total RNA was extracted from each sample as previously published 52 . Animals were fed pellets and hay daily.…”