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The timing and magnitude of the type I interferon response are correlated with disease tolerance in arbovirus infection

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Date
25/04/2023
Author
Hardy, Alexandra
Bakshi, Siddharth
Furnon, Wilhelm
MacLean, Oscar
Gu, Quan
Varjak, Margus
Varela, Mariana
Aziz, Muhamad Afiq
Shaw, Andrew E
Pinto, Rute Maria
Cameron Ruiz, Natalia
Mullan, Catrina
Taggart, Aislynn E
Da Silva Filipe, Ana
Randall, Richard E
Wilson, Sam J
Stewart, Meredith E
Palmarini, Massimo
Keywords
Arbovirus
Disease tolerance
Innate immunity
Interferons
DAS
MCP
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Abstract
Infected hosts possess two alternative strategies to protect themselves against the negative impact of virus infections: resistance, used to abrogate virus replication, and disease tolerance, used to avoid tissue damage without controlling viral burden. The 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 bluetongue disease of ruminants, as a model system to investigate the mechanisms of virus-host interactions correlating with disease tolerance. BTV induces clinical disease mainly in sheep, while cattle are considered reservoirs of infection, rarely exhibiting clinical symptoms despite sustained viremia. Using primary cells from multiple donors, we show that BTV consistently reaches higher titers in ovine cells than cells from cattle. The variable replication kinetics of BTV in sheep and cow cells were mostly abolished by abrogating the cell type I interferon (IFN) response. We identified restriction factors blocking BTV replication, but both the sheep and cow 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 than cow cells, which results in an earlier downregulation of antiviral proteins. Moreover, by using RNA sequencing (RNA-seq), we also show a more pronounced expression of interferon-stimulated genes (ISGs) in BTV-infected cow cells than 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.
Citation
Hardy , A , Bakshi , S , Furnon , W , MacLean , O , Gu , Q , Varjak , M , Varela , M , Aziz , M A , Shaw , A E , Pinto , R M , Cameron Ruiz , N , Mullan , C , Taggart , A E , Da Silva Filipe , A , Randall , R E , Wilson , S J , Stewart , M E & Palmarini , M 2023 , ' The timing and magnitude of the type I interferon response are correlated with disease tolerance in arbovirus infection ' , mBio , vol. Ahead of Print , e0010123 . https://doi.org/10.1128/mbio.00101-23
Publication
mBio
Status
Peer reviewed
DOI
https://doi.org/10.1128/mbio.00101-23
ISSN
2150-7511
Type
Journal article
Rights
Copyright © 2023 Hardy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Description
This study was funded by an Investigator Award from the Wellcome Trust (206369/Z/17/Z). Additional funding was provided by the MRC (MC_UU_12014/10; MC_UU_12014/12).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/27511

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