Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease

Costa, V. V. et al. (2022) Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease. eLife, 11, e73853. (doi: 10.7554/elife.73853) (PMID:35293862) (PMCID:PMC8959599)

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Host immune responses contribute to dengue’s pathogenesis and severity, yet the possibility that failure in endogenous inflammation resolution pathways could characterise the disease has not been contemplated. The pro-resolving protein Annexin A1 (AnxA1) is known to counterbalance overexuberant inflammation and mast cell (MC) activation. We hypothesised that inadequate AnxA1 engagement underlies the cytokine storm and vascular pathologies associated with dengue disease. Levels of AnxA1 were examined in the plasma of dengue patients and infected mice. Immunocompetent, interferon (alpha and beta) receptor one knockout (KO), AnxA1 KO, and formyl peptide receptor 2 (FPR2) KO mice were infected with dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac2-26 for analysis. In addition, the effect of Ac2-26 on DENV-induced MC degranulation was assessed in vitro and in vivo. We observed that circulating levels of AnxA1 were reduced in dengue patients and DENV-infected mice. Whilst the absence of AnxA1 or its receptor FPR2 aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestationsatteanuated the symptoms of the disease. Both clinical outcomes were attributed to modulation of DENV-mediated viral load-independent MC degranulation. We have thereby identified that altered levels of the pro-resolving mediator AnxA1 are of pathological relevance in DENV infection, suggesting FPR2/ALX agonists as a therapeutic target for dengue disease.

Item Type:Articles
Additional Information:This work received financial support from the Fapemig Hospedeiro em Dengue project, the Medical Research Council in the United Kingdom (Newton project MR/No17544/1), the National Institute of Science and Technology in Dengue and Host-microorganism Interaction (INCT dengue), a program funded by The Brazilian National Science Council (CNPq, Brazil) and Minas Gerais Foundation for Science (FAPEMIG, Brazil). JC and MP are also funded by the William Harvey Research Foundation. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) – Finance Code 001. MAS received a Newton International Fellowship from the Academy of Medical Sciences during the preparation of the manuscript. The authors also thank L'Oréal-UNESCO-ABC 'Para Mulheres na Ciência' prize granted to VVC.
Glasgow Author(s) Enlighten ID:Bonilha, Mr Caio
Creator Roles:
Bonilha, C. S.Visualization, Writing – review and editing
Authors: Costa, V. V., Sugimoto, M. A., Hubner, J., Bonilha, C. S., Queiroz-Junior, C. M., Gonçalves-Pereira, M. H., Chen, J., Gobbetti, T., Libanio Rodrigues, G. O., Bambirra, J. L., Passos, I. B., Machado Lopes, C. E., Moreira, T. P., Bonjour, K., Melo, R. C.N., Oliveira, M. A.P., Andrade, M. V. M., Sousa, L. P., Souza, D. G., Santiago, H. d. C., Perretti, M., and Teixeira, M. M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Published Online:16 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in eLife 11:e73853
Publisher Policy:Reproduced under a Creative Commons License

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