Vitamin D in malaria: more hypotheses than clues

Abstract

Vitamin D is a secosteroid hormone regulating calcium and phosphate metabolism, immune response and brain development. Low blood 25(OH)D levels have been reported in patients affected by infectious diseases caused by parasites, including malaria. Despite the high effectiveness of antimalarials, malaria is burdened with high morbidity and mortality, and the search for additional therapies is rapidly growing. Furthermore, available preventive measures have proved to be barely effective so far. Finding new prevention and therapy tools is a matter of urgency. Studies on animal models and humans have hypothesized some mechanisms by which the hormone can influence malaria pathogenesis, and the role of Vitamin D supplementation in preventing and treating this disease has been suggested. Few studies on the association between Vitamin D and malaria are available and disagreeing results have been reported. Studies in humans reporting an association between low 25(OH)D circulating levels and Malaria have a small sample size and observational study-set. Randomized controlled trials are needed in order to understand if Vitamin D administration might play a role in preventing and treating malaria.

Keywords: Biochemistry; Immunology; Infectious disease.

Fig. 1

Genomic and non-genomic actions of Vitamin D. Active Vitamin D include a nuclear receptor, VDR, and a surface receptor, MARRS, with whom 1,25(OH)2D interacts to carry out genomic and non-genomic actions. After binding the ligand, VDR forms a heterodimer with RXR receptor. VD/VDR/RXR complex interacts with VDREs, located within chromatin, resulting in genes transcription activation and genes suppression. Non-genomic actions carried out by MARRS receptors include the regulation of the activity of some proteins, like adenylyl cyclase, phospholipase C, protein kinase C, p38 MAP kinase, and the increase of Ca2+ influx through L-type voltage-gated calcium channels (L-VGCC) and Ca2+ release from intracellular stores through store-operated channels (SOC). Vitamin D Receptor: VDR; MARRS: membrane-associated rapid response steroid binding; RXR: retinoic acid receptor; VDREs: VD responsive elements; TNF-α: Tumor Necrosis Factor-α; TGF- β: Transforming Growth Factor- β; NGF: Nerve Growth Factor; L-VGCC = L-type voltage-gated calcium channels; SOC = store-operated channels; p38MAPK: 38-mitogen-activated protein kinase; PKC: Protein Kinase C.

Fig. 2

Vitamin D influence on the pathogenesis of malaria. The activity of 1,25(OH)2D has been related to the pathogenesis of malaria, due to its action on Th cells and Treg cells. The onset and progression of malaria partly depend on Th1 overwhelming response, Th2 response mitigation and Treg cells dysfunction. Active Vitamin D might influence the pathogenesis of malaria by inhibiting Th1 cells production, fostering Th2 cells differentiation and enhancing the development of Treg cells. Further, 1,25(OH)2D inhibits the syntesis of IFN-γ, TNF-α, which are involved in the development of malaria and its severe complication, CM. IFN- γ: Interferon- γ; TNF- α: Tumor Necrosis Factor α; Th: T-helper; Treg: T regulatory; CM: cerebral malaria.