Modulation of the immune response to respiratory viruses by vitamin D

Abstract

Background: Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects. Several cellular studies have investigated the effects of vitamin D metabolites on immune responses to respiratory viruses, but syntheses of these reports are lacking.

Scope: In this article, we review the literature reporting results of in vitro experiments investigating immunomodulatory actions of vitamin D metabolites in human respiratory epithelial cells infected with respiratory viruses.

Key findings: Vitamin D metabolites do not consistently influence replication or clearance of rhinovirus, respiratory syncytial virus (RSV) or influenza A virus in human respiratory epithelial cell culture, although they do modulate expression and secretion of type 1 interferon, chemokines including CXCL8 and CXCL10 and pro-inflammatory cytokines, such as TNF and IL-6.

Future research: More studies are needed to clarify the effects of vitamin D metabolites on respiratory virus-induced expression of cell surface markers mediating viral entry and bacterial adhesion to respiratory epithelial cells.

Keywords: antiviral immunity; respiratory viruses; vitamin D.

Figures

Figure 1

Pathogen recognition receptor signalling following viral infection. Ligand-induced dimerisation occurs following PAMP recognition by endosomal TLRs, which engages the Toll-IL-1 receptor (TIR) domains to initiate adaptor molecule recruitment and signal transduction. MYD88-dependent signalling results in the formation of an IRAK/TRAF6 complex, which phosphorylates IRF7 to initiate transcription of type I IFN genes, and activates a TAK1/TAB2/3 complex to drive transcription of pro-inflammatory cytokine genes via activation of NF-κB, AP1 and CREB. TRIF-dependent signalling can also activate NF-κB, AP-1 and CREB via recruitment of TRAF6 and RIP1. Alternatively, TRAF3 is recruited, resulting in phosphorylation of IRF3 which translocates into the nucleus to induce expression of type I IFNs. RIG-I and MDA5 are also able to activate NF-κB and IRF3 via interaction with IPS-1 localized on the mitochondrial membrane through homophilic interactions between their CARD domains. Similarly, CARD domains of NOD2 also interact with IPS-1 resulting in transcription of type I IFN genes. The type I IFNs produced bind to their receptor, and, via STAT-mediating signalling, initiate gene transcription.

Figure 2

Metabolism of 1α,25(OH)2D3. Vitamin D3 is either obtained from dietary sources or UV synthesis, before two hydroxylations occur to produce the active metabolite 1α,25(OH)2D3. TLR ligation can also increase levels of CYP27B1, resulting in enhanced 1α-hydroxylation of 25(OH)D3. The 1α,25(OH)2D3 then binds to nuclear or membrane vitamin D receptors (VDRs). Nuclear VDR ligation results in heterodimerization with retinoid X receptor (RXR) and binding to vitamin D responsive elements (VDRE) in promoter regions of responsive genes. Components of the RNA polymerase II complex are then recruited for induction of gene transcription, or transcription is repressed. Membrane caveolae-associated VDR ligation results in the activation of second messenger systems, with one effect being the initiation of Ras/MAPK signal transduction. Nuclear MAPK modulates gene expression and engages in cross-talk with the VDR-RXR-VDRE complex. (Adapted from Slatopolsky et al. [104], and Parton and Simons [105]).

Figure 3

The immunomodulatory actions of 1,25(OH)2D. 1,25(OH)2D has diverse and extensive effects on the immune compartment. The innate immune response is affected, with monocytes producing more LL-37 and β-defensin, with increased NOD2 expression and autophagy, while also producing diminished amounts of inflammatory cytokines, with decreased expression of TLR2 and TLR4. Differentiation into macrophages is increased, with macrophages having an increased capacity for phagocytosis and chemotaxis. However, their APC and T-cell stimulatory capacity is decreased. Monocyte and macrophage production of ROS and iNOS is able to both be induced and inhibited, thus regulating their balance. Differentiation into DCs is inhibited, with DCs expressing decreased levels of maturation surface markers. DC production of IL-12 and IL-23 is decreased, while mannose receptor expression and production of IL-10 and CCL22 are increased. When these tolerogenic DCs interact with T-cells, development of Tregs and Th2 cells is increased, with increased production of IL-10, TGF-β, IL-4 and IL-5. The development of Th1 and Th17 cells is inhibited, with decreased production of IL-2, IFN-γ and TNF-α, and attenuation of macrophage activation. B-cells are also affected by 1,25(OH)2D, demonstrating decreased immunoglobulin production, proliferation and differentiation, but increased apoptosis.

Figure 4

The immunomodulatory actions of 1,25(OH)2D against respiratory viruses. Rhinovirus infection of epithelial cells results in increased production and secretion of pro-inflammatory cytokines and chemokines, with the secretion of CXCL8 and CXCL10 further enhanced following treatment with 1,25(OH)2D. During RSV infection, IκBα expression is reduced, resulting in increased transcription of NF-κB-driven genes. STAT1 is also phosphorylated and able to translocate into the nucleus resulting in increased expression of IRF1 and IRF7. Pre-treatment with 1,25(OH)2D increases IκBα expression and decreases STAT1 phosphorylation, resulting in decreased production of CXCL10, IFN-β, MxA, ISG15, IRF1 and IRF7. Similarly, influenza A infection causes increased expression of pro-inflammatory cytokines and chemokines, with 1,25(OH)2D treatment causing decreased expression of TNF-α, IFN-β, ISG15, CXCL8, IL-6 and CCL5. Finally, 1,25(OH)2D is also able to increase LL-37 and HBD2 production, which have been shown to have antiviral effects against both RSV and influenza.