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

Hardy, A. et al. (2023) The timing and magnitude of the type I interferon response are correlated with disease tolerance in arbovirus infection. mBio, 14(3), e0010123. (doi: 10.1128/mbio.00101-23) (PMID:37097030) (PMCID:PMC10294695)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Furnon, Dr Wilhelm and Randall, Professor Richard and Wilson, Professor Sam and Aziz, Muhamad Afiq Bin and Palmarini, Professor Massimo and Taggart, Ms Aislynn and Hardy, Dr Alexandra and MacLean, Dr Oscar and Shaw, Dr Andrew and Varjak, Dr Margus and Bakshi, Dr Siddharth and Gu, Dr Quan and Da Silva Filipe, Dr Ana and Stewart, Dr Meredith and Mullan, Catrina and Cameron Ruiz, Natalia and Varela, Dr Mariana and Pinto, Dr Rute
Authors: 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., and Palmarini, M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:mBio
Publisher:American Society for Microbiology
ISSN (Online):2150-7511
Published Online:25 April 2023
Copyright Holders:Copyright © 2023 Hardy et al.
First Published:First published in mBio 14(3): e0010123
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301049Host determinants of disease outcomes in arboviral infectionsMassimo PalmariniWellcome Trust (WELLCOTR)206369/Z/17/ZIII - Centre for Virus Research
172630010Innate Immunity and Host Species Barriers (Programme 7)Massimo PalmariniMedical Research Council (MRC)MC_UU_12014/10III - Centre for Virus Research
172630015Cross-Cutting Programme - Viral Genomics and Bioinformatics (Programme 9)Andrew DavisonMedical Research Council (MRC)MC_UU_12014/12III - Centre for Virus Research