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

Vivian Vasconcelos Costa,Kennedy Bonjour,Mauro Perretti,Marcela Helena Gonçalves-Pereira,Thomas Gobbetti,Carla Elizabeth Machado Lopes,Jianmin Chen,Helton Da Costa Santiago,Marcus Vinícius Melo De Andrade ,Danielle G Souza ,Caio S Bonilha ,Ingredy Passos ,Jordana L Bambirra ,Jôsy Hubner ,Milton Adriano Pelli De Oliveira ,Lirlândia P Sousa ,Gisele Rodrigues ,Rossana C N Melo ,Thaiane Pinto Moreira ,Celso Martins Queiroz-Júnior ,Michelle A Sugimoto ,Mauro M Teixeira

doi:10.7554/elife.73853

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 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.

Highlights

Dengue is caused by one of four serotypes of dengue virus (DENV1-4) transmitted by Aedes Aegypti andA
By exploring resolution biology as a novel approach in dengue disease, both with respect to etiopathogenesis and pharmacological opportunity, we have identified that: (i) Annexin A1 (AnxA1) is downregulated in the plasma of dengue patients in comparison to healthy individuals and in Dengue virus (DENV)-infected mice in comparison to non-infected animals; (ii) depletion of the AnxA1-FPR2/ALX
Pathway aggravates clinical signs and enhances mast cell (MC) activation associated to DENV infection, indicating a nonredundant role for this resolution pathway in the pathogenesis of dengue disease; (iii) pharmacological treatment of mice with an FPR2/ALX agonistic peptide produced beneficial effects during DENV

Summary

Introduction

Dengue infection develops into a potentially lethal complication identified as severe dengue, typified by exacerbated systemic inflammation, vascular leakage, fluid accumulation, respiratory distress, severe bleeding, and/or organ impairment (WHO, 2009). Drug Administration (FDA), has its limitations, such as the increased risk for development of severe dengue in the immune populations (Huang, Tsai, Wang, Wang, & Chen, 2021; WHO, 2018)(The Lancet. The combination of these factors points to dengue as a major unmet clinical problem in countries affected by this disease (Shepard, Undurraga, Halasa, & Stanaway, 2016; Stanaway et al, 2016). The pathogenesis of severe dengue results from exacerbated host innate and adaptative immune responses to DENV. As essential regulators of vascular integrity, MC activation evoked by DENV triggers the production of inflammatory cytokines (cytokine storm) and vascular leakage, which result in hypovolemic shock in severe dengue

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