Editor – With interest, we read the paper of Weir et al about the potential association between vitamin D deficiency and COVID-19 severity.1 The authors focused on the regulation of Tregs and thrombotic pathways by vitamin D. However, we think that vitamin D binding protein (VDBP) may also play a role in severe pulmonary complications of COVID-19.
In patients with COVID-19 pneumonia, a hyperinflammatory syndrome with activation of the complement system may lead to acute respiratory distress syndrome (ARDS), in which the C5a–C5aR axis plays an important role. VDBP has been detected in the bronchoalveolar lavage fluid of ARDS patients. At sites of endothelial injury, VDBP-release augments the chemotactic effect of complement derived C5a and C5a des Arg, promoting monocyte and neutrophil attraction, aggregation and activation to generate an oxidative burst. By competing for the same binding site on VDBP, 25(OH)D3 and 1,25(OH)2D3 may inhibit this chemotaxis, thereby determining disease progression and outcome.2
Autopsy reports from COVID-19 patients have demonstrated severe endothelial injury, widespread vascular thrombosis with microangiopathy, and significant new vessel growth in the lungs. During cell death and lung tissue injury, globular actin (G-actin) is released in the extracellular compartment and polymerises into filamentous actin (F-actin). Sera from patients with ARDS contain F-actin, which may lead to the development of microembolisms, pulmonary vascular angiopathy, and multiple organ dysfunction syndrome. SARS-CoV can induce apoptosis and actin reorganization in mammalian cells under stressed conditions.3 Being members of the extracellular actin scavenger system, VDBP and gelsolin cleave actin and inhibit repolymerisation. However, elevated concentrations and/or prolonged exposure to VDBP-actin complexes may induce endothelial cell injury and death, particularly in the lung microvasculature.4
Finally, vitamin D supplementation may increase the low concentration of Tregs in COVID-19 patients.1 Activated T cells express CYP27B1 and can convert 25(OH)D3 to 1,25(OH)2D3. Significant amounts of 1,25(OH)2D3 can be produced locally by the involved immune cells during infection. However, VDBP controls T cell responses to vitamin D by sequestering 25(OH)D3 and inhibiting the production of 1,25(OH)2D3 in T cells.5
Based on these findings, we believe that further research should also focus on VDBP in COVID-19 patients.
References
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