Vitamin D, infections and immunity

Abstract

Vitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. tuberculosis. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. 1,25D is also active in signaling cascades that promote antiviral innate immunity; 1,25D-induced expression of the antimicrobial peptide CAMP/LL37, originally characterized for its antibacterial properties, is a key component of antiviral responses. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis.

Keywords: Antibacterial; Antiviral; COVID-19; Cathelicidin; Inflammation; NOD2; Vitamin D; β-defensin 2.

Fig. 1

Antibacterial activity of vitamin D in monocytic cells. Schematic representation of the antimicrobial actions of vitamin D in response to bacterial infection. In monocytic cells, there is local production of 1,25D from circulating 25D, which is under control of pattern recognition receptor signaling. 1,25D bound to the VDR regulates expression of several genes essential for innate immune defense, including those encoding cytokines, chemokines, antimicrobial peptides and pattern recognition receptors. In addition, 1,25D suppresses production of pro-inflammatory cytokines, such as IL-6, preventing an overstimulated immune response. 1,25D can also induce autophagy, resulting in enhanced bacterial killing

Fig. 2

Antiviral activity of vitamin D in a lung epithelial cell. Illustration showing events underlying vitamin D metabolism and signaling during viral infection and responses induced by 1,25D. These include induction of CAMP expression as well as 1,25D-mediated suppression of inflammatory cytokines IL-5 and IFN-γ, ICAM-1, and PAFR. The mature form of CAMP, LL37, binds to viral dsRNA, which enables efficient binding to endosomal TLR3, augmenting TLR3 signaling and subsequent viral clearance. An additional mechanism for viral removal is the induction of autophagy by 1,25D