Parasitic infections: A new frontier for PGD2 functions

Abstract

Prostaglandin (PG)D₂ is produced and/or triggered by different parasites to modulate the course of the infection. These findings position PGD2 as a therapeutic target and suggest potential beneficial effects of repositioned drugs that target its synthesis or receptor engagement. However, recent in vivo data may suggest a more nuanced role and warrants further investigation of the role of PGD2 during the full course and complexity of parasitic infections.

Fig. 1

PGD₂ synthesis and mechanism of action. (a) Arachidonic acid released from phospholipids by a Phospholipase (PL)A₂ is metabolized by either the constitutive cyclooxygenase (COX)-1 or the inflammatory mediator inducible COX-2. Hematopoietic (h)PGD synthase is the final enzymatic step to produce PGD₂ in immune cells such as mast cells, eosinophils, basophils, TH2 cells and dendritic cells. (b) Once produced PGD₂ may act on two G-protein coupled receptors: DP1 and DP2, that trigger distinct signaling pathways that may act cooperatively or antagonistically to regulate different cell functions. Hence, PGD₂ can modulate Allergic reactions and other type 2 immune responses.

Fig. 2

Participation of PGD₂ in protozoan infection. (a) PGD₂ is produced autonomously by different types of protozoan parasites and (b) its production can be triggered in immune cells in response to parasite-derived signals. (c) The subsequent increases in PGD₂ levels in bodily fluids may impact the parasite and the host cells regulating parasite burden and symptoms.

Fig. 3

Role of PGD₂ in helminth infection. (a) Helminths express a PGD synthase ortholog that can synthetize PGD₂. (b) Helminths can trigger PGD₂ production by host cell through activation of Pattern Recognition Receptors or direct tissue damage. The increase in PGD₂ facilitates the parasite's escape from the host immune response and increases infection burden.

Fig. 4

PGD₂ suitability as a therapeutic target. (a) Antagonism of DP2 receptor has been shown to be a safe therapeutic approach to allergic conditions. (b) The use of DP2 antagonists has also been suggested for the treatment of diseases where PGD₂ plays a non-canonical role, including neglected infectious diseases. Thus, repositioning of such drug may provide a relevant alternative for other conditions on which PGD₂ is described to have a role. Due to the complex nature of parasite infections that include different evolutive forms of the parasites and an ever-changing immune response landscape, caution should be exercised so the therapeutic intervention is employed where and when it will produce the desired outcome.