Bryden, SR, Pingen, M orcid.org/0000-0001-5689-9076, Lefteri, DA et al. (16 more authors) (2020) Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site. Science Translational Medicine, 12 (527). eaax2421. ISSN 1946-6234
Abstract
Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the Alphavirus, Flavivirus, and Orthobunyavirus genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.
Metadata
Item Type: | Article |
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Copyright, Publisher and Additional Information: | © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on Vol. 12, Issue 527, 22 Jan 2020, DOI: 10.1126/scitranslmed.aax2421. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Virology 2 (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Infection and Immunity (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 108227/B/15/Z MRC MR/R014574/1 Royal Society RGS\R1|191390 MRC MR/N01054X/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Jan 2020 12:02 |
Last Modified: | 23 Jan 2020 12:03 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Identification Number: | 10.1126/scitranslmed.aax2421 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155298 |
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