Host-directed therapeutic strategies against apicomplexan parasites: targeting purinergic P2 receptors

Apicomplexan parasites establish intracellular infections that profoundly alter host cell physiology and elicit complex immune responses. The long-standing coevolution between these parasites and vertebrate hosts has resulted in extensive overlap between parasite and host metabolic pathways, limiting the feasibility of conventional parasite-centered therapeutic approaches. Increasing evidence indicates that host-derived signals generated during infection play a decisive role in shaping parasite survival and dissemination. Among these signals, extracellular nucleotides released in response to cellular stress and tissue damage have emerged as key modulators of innate immune responses. These molecules are sensed by purinergic P2 receptors, which integrate danger signals with inflammatory and microbicidal pathways. This review examines how purinergic signaling contributes to host–parasite interactions during apicomplexan infections, with particular emphasis on Toxoplasma gondii and Plasmodium spp. We discuss the dual role of P2 receptors in coordinating immune responses and directly affecting parasite viability, highlighting their potential as targets for host-directed therapeutic strategies.