Vitamin D Modulation of the Innate Immune Response to Paediatric Respiratory Pathogens Associated with Acute Lower Respiratory Infections

Abstract

Vitamin D is an essential component of immune function and childhood deficiency is associated with an increased risk of acute lower respiratory infections (ALRIs). Globally, the leading childhood respiratory pathogens are Streptococcus pneumoniae, respiratory syncytial virus and the influenza virus. There is a growing body of evidence describing the innate immunomodulatory properties of vitamin D during challenge with respiratory pathogens, but recent systematic and unbiased synthesis of data is lacking, and future research directions are unclear. We therefore conducted a systematic PubMed literature search using the terms "vitamin D" and "Streptococcus pneumoniae" or "Respiratory Syncytial Virus" or "Influenza". A priori inclusion criteria restricted the review to in vitro studies investigating the effect of vitamin D metabolites on human innate immune cells (primary, differentiated or immortalised) in response to stimulation with the specified respiratory pathogens. Eleven studies met our criteria. Despite some heterogeneity across pathogens and innate cell types, vitamin D modulated pathogen recognition receptor (PRRs: Toll-like receptor 2 (TLR2), TLR4, TLR7 and nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)) expression; increased antimicrobial peptide expression (LL-37, human neutrophil peptide (HNP) 1-3 and β-defensin); modulated autophagosome production reducing apoptosis; and modulated production of inflammatory cytokines (Interleukin (IL) -1β, tumour necrosis factor-α (TNF-α), interferon-ɣ (IFN-ɣ), IL-12p70, IFN-β, Regulated on Activation, Normal T cell Expressed (RANTES), IL-10) and chemokines (IL-8 and C-X-C motif chemokine ligand 10 (CXCL10)). Differential modulation of PRRs and IL-1β was reported across immune cell types; however, this may be due to the experimental design. None of the studies specifically focused on immune responses in cells derived from children. In summary, vitamin D promotes a balanced immune response, potentially enhancing pathogen sensing and clearance and restricting pathogen induced inflammatory dysregulation. This is likely to be important in controlling both ALRIs and the immunopathology associated with poorer outcomes and progression to chronic lung diseases. Many unknowns remain and further investigation is required to clarify the nuances in vitamin D mediated immune responses by pathogen and immune cell type and to determine whether these in vitro findings translate into enhanced immunity and reduced ALRI in the paediatric clinical setting.

Keywords: Streptococcus pneumoniae; acute lower respiratory infections; influenza virus; innate immunity; respiratory syncytial virus; vitamin D.

Figure 1

Vitamin D metabolism and receptor binding. Vitamin D is obtained from dietary sources, supplementation or is converted from 7-dehydrocholesterol in the skin by ultraviolet B (UVB) rays. Vitamin D is then converted to the major circulating form, 25(OH)D₃, by 25-hydroxylase (CYP2R1) in the liver. The active circulating form, 1,25(OH)₂D₃, is largely synthesised in the kidney by 1-α-hydroxylase (CYP27B1), but also by many innate immune cells. 1,25(OH)₂D₃ ligates with cytosolic or membrane bound vitamin D receptor (VDR) and can also be catabolised by 24-hydroxylase (CYP24A1). VDR ligation results in heterodimerisation with retinoid X receptor (RXR), translocation of this complex to the nucleus and binding to vitamin D response elements (VDRE) in the promotor regions of responsive genes results in up and down-regulation of gene transcription involved in the innate immune response. Non-genomic effects can occur when membrane bound VDR ligation occurs, inducing acute activation of cell signalling pathways (mitogen-activated protein kinase, MAPK and phosphatidylinositol, PI3K). These signalling cascades can alter gene transcription via crosstalk with secondary messengers. (Adapted from Mann et al. [50] and Haussler et al. [51]). (Created with BioRender.com [52]).

Figure 2

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram depicting the systematic study selection process. S. pneumoniae: Streptococcus pneumoniae, RSV: Respiratory Syncytial Virus.

Figure 3

Effects of vitamin D on innate cell subsets in response to Streptococcus pneumoniae (S. pneumoniae). Vitamin D differentially modulates expression of pathogen recognition receptors, toll-like receptor 2 (TLR2), TLR4, CD14 and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) on neutrophils, monocytes, dendritic cells (DCs) and peripheral blood mononuclear cells (PBMCs) altering their pathogen sensing capacity. Vitamin D increases production of IL-4 in neutrophils, decreasing apoptosis, whilst also increasing production of suppressor of cytokine signalling 1 (SOCS-1) and SOCS-3, reducing tumour necrosis factor receptor-associated factor 6 (TRAF6) and nuclear factor kappa B (NFκB), overall reducing excessive inflammation (IL-6, IL-8, IL-12p70). Vitamin D modulates TNF-α, IFN-ɣ, IL-8 and IL-10 in monocytes and PBMCs and IL-1β is differentially modulated in PBMCs and DCs, potentially contributing to initiation of the inflammatory process (IL-1β), but overall reducing excessive inflammation. Production of human beta-defensin 3 (hBD-3) within DCs and human neutrophil peptide (HNP1-3) and LL-37 within neutrophils is enhanced by treatment with vitamin D, potentially increasing anti-bacterial capacity. Finally, the maturation and migration (CD86 and C-C chemokine receptor type 7 (CCR7)) of DCs is upregulated by vitamin D, priming these cells for interactions with adaptive immunity. ↑/↓ indicates increase or decrease and → indicates no difference/change to response during immune stimulation with versus without the experimental addition of vitamin D. Green arrows indicate potential net effect. (Created with BioRender.com [52]).

Figure 4

Effects of vitamin D on innate cell subsets in response to respiratory syncytial virus (RSV). Vitamin D differentially modulates expression of pathogen recognition receptors, CD14, toll-like receptor 2 (TLR2), TLR4 and TLR7 on monocytes, natural kills (NK) cells and peripheral blood mononuclear cells (PBMCs) altering their pathogen sensing capacity. Vitamin D increases inhibitor of kappa B alpha (IκBα) and decreases signal transducer and activator of transcription (STAT1) phosphorylation in respiratory epithelial cells, resulting in decreased production of the chemokine; C-X-C motif chemokine ligand 10 (CXCL10) and of antiviral agents; interferon-β (IFN-β), myxovirus resistance protein A (MxA), IFN-stimulated protein of 15kDa (ISG15), IFN regulatory factor 1 (IRF1) and IFR7, overall potentially reducing inflammation. Cathelicidin expression within respiratory epithelial cells is increased by vitamin D, potentially increasing anti-viral capacity. Vitamin D reduces IL-6 in PBMCs but has not impact on IFN-ɣ, IL-1β, IL-10, C-C motif chemokine ligand 2 (CCL2), CCL8, and CCL5. ↑/↓ indicates increase or decrease and → indicates no difference/change to response during immune stimulation with versus without the experimental addition of vitamin D. Green arrows indicate potential net effect. (Created with BioRender.com [52]).