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.
Reviewing Editor
- Frank Kirchhoff, Ulm University Medical Center, Germany
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.
Version history
- Received: September 14, 2021
- Preprint posted: November 3, 2021 (view preprint)
- Accepted: March 15, 2022
- Accepted Manuscript published: March 16, 2022 (version 1)
- 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.
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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
Further reading
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- Cell Biology
- Immunology and Inflammation
Cytokine polyfunctionality is a well-established concept in immune cells, especially T cells, and their ability to concurrently produce multiple cytokines has been associated with better immunological disease control and subsequent effectiveness during infection and disease. To date, only little is known about the secretion dynamics of those cells, masked by the widespread deployment of mainly time-integrated endpoint measurement techniques that do not easily differentiate between concurrent and sequential secretion. Here, we employed a single-cell microfluidic platform capable of resolving the secretion dynamics of individual PBMCs. To study the dynamics of poly-cytokine secretion, as well as the dynamics of concurrent and sequential polyfunctionality, we analyzed the response at different time points after ex vivo activation. First, we observed the simultaneous secretion of cytokines over the measurement time for most stimulants in a subpopulation of cells only. Second, polyfunctionality generally decreased with prolonged stimulation times and revealed no correlation with the concentration of secreted cytokines in response to stimulation. However, we observed a general trend towards higher cytokine secretion in polyfunctional cells, with their secretion dynamics being distinctly different from mono-cytokine-secreting cells. This study provided insights into the distinct secretion behavior of heterogenous cell populations after stimulation with well-described agents and such a system could provide a better understanding of various immune dynamics in therapy and disease.
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
