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.

Reviewing Editor

  1. Frank Kirchhoff, Ulm University Medical Center, Germany

Publication history

  1. Received: September 14, 2021
  2. Preprint posted: November 3, 2021 (view preprint)
  3. Accepted: March 15, 2022
  4. Accepted Manuscript published: March 16, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

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.

Metrics

  • 997
    Page views
  • 153
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  1. Further reading

Further reading

    1. Immunology and Inflammation
    Lyra O Randzavola, Paige M Mortimer ... David C Thomas
    Research Article

    EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Mingyao Pan, Bo Li
    Short Report Updated

    T cells are potent at eliminating pathogens and playing a crucial role in the adaptive immune response. T cell receptor (TCR) convergence describes T cells that share identical TCRs with the same amino acid sequences but have different DNA sequences due to codon degeneracy. We conducted a systematic investigation of TCR convergence using single-cell immune profiling and bulk TCRβ-sequence (TCR-seq) data obtained from both mouse and human samples and uncovered a strong link between antigen-specificity and convergence. This association was stronger than T cell expansion, a putative indicator of antigen-specific T cells. By using flow-sorted tetramer+ single T cell data, we discovered that convergent T cells were enriched for a neoantigen-specific CD8+ effector phenotype in the tumor microenvironment. Moreover, TCR convergence demonstrated better prediction accuracy for immunotherapy response than the existing TCR repertoire indexes. In conclusion, convergent T cells are likely to be antigen-specific and might be a novel prognostic biomarker for anti-cancer immunotherapy.