Formyl peptide receptor (fpr) as a therapeutic target in the treatment of severe malaria

Malaria is the leading parasitic disease in terms of morbidity and mortality worldwide, especially in developing countries, where it contributes to the perpetuation of poverty and hinders economic growth. In addition to cerebral symptoms, malaria is a complex disorder that can result in acute lung injury (ALI), acute kidney injury (AKI), and multiple organ dysfunction. ALI has been observed in patients with cerebral malaria, occurring in 5% of mild cases and 20–30% of cerebral malaria cases. Similarly, AKI can affect up to 60% of malaria cases in endemic regions. These complications are largely driven by intense tissue damage and inflammatory responses. For instance, ALI and AKI during severe malaria are associated with leukocyte accumulation, T lymphocyte infiltration, reduced expression of sodium channels in lung tissue, altered vascular permeability, and increased chemokine production in renal tissue.

Experimental models of severe malaria have shown morphological changes in kidney tissue, altered urinary flow, and reduced creatinine clearance, with persistent inflammation observed even after antimalarial treatment and parasitemia clearance. This indicates that addressing the inflammatory response alongside antimalarial therapy may be necessary for full recovery. Adjuvant anti-inflammatory strategies have been proposed, including nitric oxide donors, but none have proven completely effective. In this context, omega-3-derived specialized pro-resolving mediators (SPMs)—agonists of the formyl peptide receptor (FPR) family—may serve as promising adjunctive therapies. These mediators, derived from DHA, AA, and EPA, are known to modulate inflammation and promote resolution through mechanisms such as leukocyte apoptosis and enhanced phagocytosis. FPRs also interact with peptide ligands like Annexin A1, which prevents leukocyte adhesion and migration to inflamed tissues.

SPMs have demonstrated beneficial effects on ALI and AKI in various disease models, although their role in experimental malaria remains underexplored. Preliminary work has shown that treatment with LXA4, a well-characterized SPM, increases survival in P. berghei-infected mice by activating cytoprotective pathways in the brain. These findings suggest that FPR pathways may represent important therapeutic targets for treating malaria-associated organ damage.

Basic Science
Drug-based Strategies

Nov 2017 — May 2021

Brazil