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 <i>P. falciparum</i> stimulates B cells to produce OPG <i>in vitro</i>, and that B cell OPG production is increased <i>ex vivo</i> 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.
Authors
- Fiona H. Amante (ORCID: https://orcid.org/0000-0002-7788-5885)
- John Woodford (ORCID: https://orcid.org/0000-0002-8363-5495)
- Jessica R. Loughland (ORCID: https://orcid.org/0000-0003-2253-1577)
- Arya Sheela Nair (ORCID: https://orcid.org/0000-0002-2662-5709)
- Timothy William (ORCID: https://orcid.org/0000-0002-2195-6736)
- Matthew J. Grigg (ORCID: https://orcid.org/0000-0001-9914-8352)
- Bridget E. Barber (ORCID: https://orcid.org/0000-0003-1066-7960)
- Kim A. Piera (ORCID: https://orcid.org/0000-0002-7414-9604)
- Dean W. Andrew (ORCID: https://orcid.org/0000-0001-6528-5439)
- Michelle J. Boyle (ORCID: https://orcid.org/0000-0002-0268-232X)
- J. S. McCarthy
- Nicholas M. Anstey
Institutions
- Burnet Institute (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Royal Brisbane and Women's Hospital (AU)
- Charles Darwin University (AU)
- Menzies School of Health Research (AU)
- Peter Doherty Institute (AU)
- National Institute of Allergy and Infectious Diseases (US)
- Subang Jaya Medical Centre (MY)
Publication Details
- Journal
- iScience
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1016/j.isci.2025.112768
- Primary Topic
- Bone Metabolism and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Medicines for Malaria Venture
- Kementerian Kesihatan Malaysia
- National Institutes of Health
- National Health and Medical Research Council