Role of vitamin D in regulating COVID-19 severity-An immunological perspective

Abstract

Vitamin D, a key nutrient/prohormone classically associated with skeletal health, is also an important immunomodulator, with pleotropic effects on innate and adaptive immune cells. Outcomes of several chronic, autoimmune, and infectious diseases are linked to vitamin D. Emergent correlations of vitamin D insufficiency with coronavirus-induced disease 2019 (COVID-19) severity, alongside empirical and clinical evidence of immunoregulation by vitamin D in other pulmonary diseases, have prompted proposals of vitamin D supplementation to curb the COVID-19 public health toll. In this review paper, we engage an immunological lens to discuss potential mechanisms by which vitamin D signals might regulate respiratory disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, vis a vis other pulmonary infections. It is proposed that vitamin D signals temper lung inflammatory cascades during SARS-CoV2 infection, and insufficiency of vitamin D causes increased inflammatory cytokine storm, thus leading to exacerbated respiratory disease. Additionally, analogous to studies of reduced cancer incidence, the dosage of vitamin D compounds administered to patients near the upper limit of safety may serve to maximize immune health benefits and mitigate inflammation and disease severity in SARS-CoV2 infections. We further deliberate on the importance of statistically powered clinical correlative and interventional studies, and the need for in-depth basic research into vitamin D-dependent host determinants of respiratory disease severity.

Keywords: immunoregulation; vitamin D.

Graphical Abstract

FIGURE 1

Model of immunomodulation by vitamin D in COVID-19. The decreasing green shaded triangle indicates decreasing vitamin D status. Increasing intensity of red shade indicates increasing inflammation with decreasing vitamin D levels. Infection in vitamin D sufficient hosts (green half of the figure, corresponding to serum levels of 25(OH)D > 25–30 ng/ml, defined as sufficient) is expected to induce optimal activation of innate immune cells such as macrophages (with robust antimicrobial peptide, AMP, production) and DCs with robust up-regulation of MHC and costimulatory molecules, and regulated production of proinflammatory cytokines. Balanced differentiation of effector CD8 and CD4 T cell subsets under conditions of vitamin D sufficiency is also expected to promote robust antiviral responses, with regulated production of inflammatory cytokines. Vitamin D sufficiency is also predicted to promote the development of immunoprotective NK-T cells, and maintain epithelial junctional integrity and endothelial vascular permeability, thus minimizing pulmonary damage. Contrarily, host vitamin D insufficiency or deficiency (red half of the figure, corresponding to serum levels of 25(OH)D  ≤ 10 ng/ml (25 nM) defined as deficient, and 10–20 ng/ml defined as insufficient) is expected to lead to aberrant activation of innate inflammatory mediators such as macrophages and DCs, leading to exacerbated inflammation, more pronounced expansion and terminal differentiation of effector CD8 and inflammatory CD4 T cell subsets, and diminished Treg induction and NK-T cell development. Likewise, the junctional integrity of lung epithelial and vascular endothelial cells is also predicted to be impaired, thus leading to pulmonary edema, lung injury and functional impairment and ARDS. Conditions of vitamin D hyper-supplementation are not depicted in this model. A better understanding of disease-context-dependent immunomodulatory effects of vitamin D in SARS-CoV2 infections at pulmonary sites of viral growth and secondary lymphoid sites of immune activation will illuminate potential beneficial effects of normalizing vitamin D levels to sufficient or hyper-supplemented levels