Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease
- Universidade Federal de Minas Gerais, Brazil
- Queen Mary University of London, United Kingdom
- Federal University of Juiz de Fora, Brazil
- Universidade Federal de Goiás, Brazil
Abstract
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 1 knockout (KO), AnxA1 KO and FPR2 KO mice were infected with Dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac2-26 for analysis. Additionally, 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. While the absence of AnxA1 or its receptor FPR2 aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestations. 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.
Data availability
All data has been included in the manuscript, and source data files have been provided for Figures 1-6.
Article and author information
Author details
Vivian Vasconcelos Costa
Michelle A Sugimoto
Lirlândia Pires Sousa
Mauro Martins Teixeira
Funding
Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Fapemig Hospedeiro em Dengue project)
- Mauro Martins Teixeira
Medical Research Council (MR/No17544/1)
- Lirlândia Pires Sousa
- Danielle Gloria Souza
- Helton da Costa Santiago
- Mauro Perretti
- Mauro Martins Teixeira
Conselho Nacional de Desenvolvimento Científico e Tecnológico (Instituto Nacional de Ciência e Tecnologia em Dengue)
- Lirlândia Pires Sousa
- Danielle Gloria Souza
- Mauro Martins Teixeira
Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Instituto Nacional de Ciência e Tecnologia em Dengue)
- Lirlândia Pires Sousa
- Danielle Gloria Souza
- Mauro Martins Teixeira
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001)
- Michelle A Sugimoto
- Mauro Martins Teixeira
L'Oréal-UNESCO-ABC (Para Mulheres na Ciência prize")
- Vivian Vasconcelos Costa
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Pós-Doutorado/Capes (PNPD /CAPES))
- Michelle A Sugimoto
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the Brazilian Government's ethical and animal experiments regulations (Law 11794/2008) and the recommendations of the CONCEA (Conselho Nacional de Controle de Experimentação Animal) from Brazil. All animal experiments received prior approval from the Animal Ethics Committee (CEUA) of Universidade Federal de Minas Gerais (UFMG), Brazil (Protocol numbers: 169/2016 and 234/2019). All surgeries were performed under ketamine/xylazine anaesthesia, and every effort was made to minimise animal suffering.
Human subjects: Human sample collection was approved by the Committee on Ethics in Research of the Universidade Federal de Minas Gerais (Protocol Numbers 24832513.4.0000.5149 and 66128617.6.0000.5149). All patients have provided signed informed consent.
Copyright
© 2022, Costa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease
eLife 11:e73853.
https://doi.org/10.7554/eLife.73853
