Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease
Year: 2022
Type: article
Abstract: 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, IFNα/βR -/- , AnxA1 -/- and FPR2/ALX -/- mice were infected with Dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac 2-26 for analysis. Additionally, the effect of Ac 2-26 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/ALX 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.
Source: eLife
DOI: 10.7554/elife.73853
Authors: Vivian V Costa, Michelle A Sugimoto, Josy Hubner, Caio S Bonilha, Celso M Queiroz-Junior, Marcela Helena Gonçalves Pereira, Jianmin Chen, Thomas Gobbetti, Gisele Olinto Libanio Rodrigues, Jordana L. Bambirra, Ingredy Passos, Carla Elizabeth Machado Lopes, Thaiane P. Moreira, Kennedy Bonjour, Rossana C. N. Melo, Milton A. P. Oliveira, Marcus Vinicius M. Andrade, Lirlândia Pires Sousa, Danielle Gloria Souza, Helton da Costa Santiago, Mauro Perretti, Mauro Martins Teixeira
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4226342464