Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model

Bryden, S. R. et al. (2022) Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model. PNAS Nexus, 1(1), pgac024. (doi: 10.1093/pnasnexus/pgac024)

[img] Text
266474.pdf - Published Version
Available under License Creative Commons Attribution.

7MB

Abstract

Dabie bandavirus (previously severe fever with thrombocytopenia syndrome virus; SFTSV) is an emerging tick-borne bunyavirus responsible for severe fever with thrombocytopenia syndrome (SFTS), a disease with high case fatality that is characterised by high fever, thrombocytopenia, and potentially lethal haemorrhagic manifestations. Currently, neither effective therapeutic strategies nor approved vaccines exist for SFTS. Therefore, there remains a pressing need to better understand the pathogenesis of the disease and to identify therapeutic strategies to ameliorate SFTS outcomes. Using a type I interferon (IFN)-deficient mouse model, we investigated the viral tropism, disease kinetics and the role of the virulence factor non-structural protein (NSs) in SFTS. Ly6C+ MHCII+ cells in the lymphatic tissues were identified as an important target cell for SFTSV. Advanced SFTS was characterised by significant migration of inflammatory leukocytes, notably neutrophils, into the lymph node and spleen, however, these cells were not required to orchestrate the disease phenotype. The development of SFTS was associated with significant upregulation of pro-inflammatory cytokines, including high levels of IFN-γ and IL-6 in the serum, lymph node and spleen. Humoral immunity generated by inoculation with delNSs SFTSV was 100% protective. Importantly, NSs was critical to the inhibition of the host IFNɣ response or downstream interferon stimulated gene production and allowed for the establishment of severe disease. Finally, therapeutic but not prophylactic use of anti-IL-6 antibodies significantly increased the survival of mice following SFTSV infection and therefore this treatment modality presents a novel therapeutic strategy for treating severe SFTS.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bryden, Dr Steven and Fares, Dr Mazigh and Willett, Professor Brian and Clarke, Mr Andrew and Brennan, Dr Benjamin and Dunlop, Dr James and Pingen, Dr Marieke and Patel, Professor Arvind and Kohl, Professor Alain
Creator Roles:
Bryden, S. R.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Dunlop, J. I.Investigation, Writing – review and editing
Clarke, A. T.Data curation, Formal analysis, Investigation, Visualization, Writing – review and editing
Fares, M.Investigation, Writing – review and editing
Pingen, M.Conceptualization, Funding acquisition, Methodology, Resources, Writing – review and editing
Willett, B. J.Conceptualization, Methodology, Writing – review and editing
Patel, A. H.Conceptualization, Funding acquisition, Methodology, Writing – review and editing
Kohl, A.Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing – review and editing
Brennan, B.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Authors: Bryden, S. R., Dunlop, J. I., Clarke, A. T., Fares, M., Pingen, M., Wu, Y., Willett, B. J., Patel, A. H., Gao, G. F., Kohl, A., and Brennan, B.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:PNAS Nexus
Publisher:Oxford University Press
ISSN:2752-6542
ISSN (Online):2752-6542
Published Online:10 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in PNAS Nexus 1(1): pgac024
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.5525/gla.researchdata.1179

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301938Vaccines and molecular tools for the control of the emerging bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV)Alain KohlBiotechnology and Biological Sciences Research Council (BBSRC)BB/R019800/1III - Centre for Virus Research
172630007Arthropod-borne infections and emerging virus infections in high risk areas (Programme 4)Alain KohlMedical Research Council (MRC)MC_UU_12014/8III - Centre for Virus Research
172630Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2III - Centre for Virus Research
301176What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vectorBenjamin BrennanWellcome Trust (WELLCOTR)210462/Z/18/ZIII - Centre for Virus Research