Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site

Bryden, S. R. et al. (2020) Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site. Science Translational Medicine, 12(527), eaax2421. (doi: 10.1126/scitranslmed.aax2421) (PMID:31969486)

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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 , , and 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.

Item Type:Articles
Additional Information:Funding was provided by BBSRC DTP PhD fellowship to S.R.B. and C.S.M.; Wellcome Trust Seed Award in Science (108227/B/15/Z), The Royal Society research grant (RGS\R1\191390), and the University of Leeds UAF to C.S.M.; Wellcome Trust investigator award, MRC Programme, and a Wolfson Royal Society Merit Award to G.J.G.; MRC core funding MC_UU_12014/8 to E.P.; Fund for Scientific Research (FWO) Flanders individual credit (1522918N) to L.D. and FWO PhD fellowship (1S21918N) to S.J.; and an MRC grant MR/NO1054X/1 to A.T.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bryden, Dr Steven and Pondeville, Dr Emilie and Edgar, Dr Julia and Varjak, Dr Margus and Major, Mr Jack and Pingen, Dr Marieke and Graham, Professor Gerard
Authors: Bryden, S. R., Pingen, M., Lefteri, D. A., Miltenburg, J., Delang, L., Jacobs, S., Abdelnabi, R., Neyts, J., Pondeville, E., Major, J., Müller, M., Khalid, H., Tuplin, A., Varjak, M., Merits, A., Edgar, J., Graham, G. J., Shams, K., and McKimmie, C. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Translational Medicine 12(527):eaax2421
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
Medical Research Council (MRC)MC_UU_12014/8