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

  1. Vivian Vasconcelos Costa

    Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0175-642X
  2. Michelle A Sugimoto

    Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4527-6065
  3. Josy Hubner

    Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  4. Caio S Bonilha

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  5. Celso Martins Queiroz-Junior

    Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  6. Marcela Helena Gonçalves-Pereira

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  7. Jianmin Chen

    Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Thomas Gobbetti

    Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. Gisele Olinto Libanio Rodrigues

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  10. Jordana L Bambirra

    Department of Microbiology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  11. Ingredy B Passos

    Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  12. Carla Elizabeth Machado Lopes

    Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  13. Thaiane P Moreira

    Department of Microbiology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  14. Kennedy Bonjour

    Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
    Competing interests
    No competing interests declared.
  15. Rossana CN Melo

    Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
    Competing interests
    No competing interests declared.
  16. Milton AP Oliveira

    Tropical Pathology and Public Health Institute, Universidade Federal de Goiás, Goiania, Brazil
    Competing interests
    No competing interests declared.
  17. Marcus Vinicius M Andrade

    School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  18. Lirlândia Pires Sousa

    School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1042-9762
  19. Danielle Gloria Souza

    Department of Microbiology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  20. Helton da Costa Santiago

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    No competing interests declared.
  21. Mauro Perretti

    Queen Mary University of London, London, United Kingdom
    For correspondence
    m.perretti@qmul.ac.uk
    Competing interests
    Mauro Perretti, MP is on the Scientific Advisory Board of ResoTher Pharma AS, which is interested in developing Annexin A1-derived peptides for cardiovascular settings..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2068-3331
  22. Mauro Martins Teixeira

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    For correspondence
    mmtex.ufmg@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6944-3008

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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  1. Vivian Vasconcelos Costa
  2. Michelle A Sugimoto
  3. Josy Hubner
  4. Caio S Bonilha
  5. Celso Martins Queiroz-Junior
  6. Marcela Helena Gonçalves-Pereira
  7. Jianmin Chen
  8. Thomas Gobbetti
  9. Gisele Olinto Libanio Rodrigues
  10. Jordana L Bambirra
  11. Ingredy B Passos
  12. Carla Elizabeth Machado Lopes
  13. Thaiane P Moreira
  14. Kennedy Bonjour
  15. Rossana CN Melo
  16. Milton AP Oliveira
  17. Marcus Vinicius M Andrade
  18. Lirlândia Pires Sousa
  19. Danielle Gloria Souza
  20. Helton da Costa Santiago
  21. Mauro Perretti
  22. Mauro Martins Teixeira
(2022)
Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease
eLife 11:e73853.
https://doi.org/10.7554/eLife.73853

Share this article

https://doi.org/10.7554/eLife.73853

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