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) (PMID:35529317) (PMCID:PMC9071185)
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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 Dunlop, Dr James and Willett, Professor Brian and Clarke, Mr Andrew and Brennan, Dr Benjamin and Patel, Professor Arvind and Pingen, Dr Marieke 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 Infection & Immunity > Centre for Virus Research College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| 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 |
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