Osteoprotegerin and its ligands RANKL and TRAIL in falciparum, vivax, and knowlesi malaria

Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of NF-ƙB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), is increasingly recognized as a marker of poor prognosis in cardiovascular disease. Here, we demonstrate that in adults with falciparum and vivax malaria, OPG is increased, and its ligands TRAIL and RANKL decreased, in association with validated markers of disease severity. Using longitudinal samples from malaria volunteer infection studies, we demonstrate that TRAIL is unexpectedly increased in early infection, suggesting binding of OPG to RANKL prior to TRAIL. Finally, in addition to its known vascular origin, we show that P. falciparum stimulates B cells to produce OPG in vitro, and that B cell OPG production is increased ex vivo in patients with falciparum, vivax, and knowlesi malaria. Our findings provide evidence of the importance of the OPG/RANKL/TRAIL pathway in pathogenesis of acute systemic inflammatory and microvascular diseases, with implications for adjunctive therapies.