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

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Vitamin D Modulation of the Innate Immune Response to Paediatric Respiratory Pathogens Associated with Acute Lower Respiratory Infections nutrients Review Vitamin D Modulation of the Innate Immune Response to Paediatric Respiratory Pathogens Associated with Acute Lower Respiratory Infections Amy S. Bleakley 1,*, Paul V. Licciardi 2 and Michael J. Binks 1,* 1 Child Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT 0810, Australia 2 Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia; [email protected] * Correspondence: [email protected] (A.S.B.); [email protected] (M.J.B.); Tel.: +61-88946-8402 (A.S.B.); +61-88946-8508 (M.J.B.) 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 prop- erties 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), Citation: Bleakley, A.S.; Licciardi, TLR4, TLR7 and nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)) expres- P.V.; Binks, M.J. Vitamin D sion; increased antimicrobial peptide expression (LL-37, human neutrophil peptide (HNP) 1-3 and Modulation of the Innate Immune β-defensin); modulated autophagosome production reducing apoptosis; and modulated production Response to Paediatric Respiratory of inflammatory cytokines (Interleukin (IL) -1β, tumour necrosis factor-α (TNF-α), interferon-G Pathogens Associated with Acute G β Lower Respiratory Infections. (IFN- ), IL-12p70, IFN- , Regulated on Activation, Normal T cell Expressed (RANTES), IL-10) and Nutrients 2021, 13, 276. https://doi. chemokines (IL-8 and C-X-C motif chemokine ligand 10 (CXCL10)). Differential modulation of PRRs org/10.3390/nu13010276 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. Received: 7 January 2021 In summary, vitamin D promotes a balanced immune response, potentially enhancing pathogen Accepted: 18 January 2021 sensing and clearance and restricting pathogen induced inflammatory dysregulation. This is likely to Published: 19 January 2021 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 Publisher’s Note: MDPI stays neutral required to clarify the nuances in vitamin D mediated immune responses by pathogen and immune with regard to jurisdictional claims in cell type and to determine whether these in vitro findings translate into enhanced immunity and published maps and institutional affil- reduced ALRI in the paediatric clinical setting. iations. Keywords: vitamin D; innate immunity; acute lower respiratory infections; Streptococcus pneumoniae; respiratory syncytial virus; influenza virus Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and 1.1. Background conditions of the Creative Commons Attribution (CC BY) license (https:// Acute lower respiratory infections (ALRI) are a leading cause of hospitalisation and creativecommons.org/licenses/by/ death in children under-5 globally [1]. The greatest burden occurs in low- and middle- 4.0/). income countries and among socioeconomically disadvantaged populations in high-income Nutrients 2021, 13, 276. https://doi.org/10.3390/nu13010276 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, 276 2 of 24 countries such as First Nations populations [2]. Early and recurrent ALRIs are also the leading modifiable risk factor for the development of chronic lung diseases which can reduce life expectancy [3]. Slow progress in addressing the social determinants of health drives the need for novel, effective, evidence-based interventions to prevent and/or delay early onset ALRIs. The most common ALRI presentations in children are acute bronchitis, bronchiolitis, and pneumonia. The key aetiological pathogens include the Gram-positive bacterium Streptococcus pneumoniae (S. pneumoniae) [4], respiratory syncytial virus (RSV) [5] and influenza virus [6]. Recently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) has caused pandemic infections and is likely to remain a prominent cause of ALRIs moving forward, though mostly in adults [7]. While most of the disease caused by ALRI pathogens is not vaccine preventable, some pathogen specific vaccines are available, such as the pneumococcal conjugate vaccine (PCV) [8] and the inactivated influenza vaccine (IIV) [9]. However, current PCVs only cover up to 13 of the more than 100 S. pneumoniae serotypes [10,11] and the IIV is only moderately effective due to annual strain changes in the influenza A virus (IAV) and it is not commonly given to infants [12]. RSV [13] and SARS-CoV-2 [14,15] vaccines are currently under development and may be available in the future. Broader approaches that build infant resilience by supporting optimal immune function are vital. In this context, vitamin D is an important micronutrient with immunomodulatory properties, yet vitamin D deficiency (<50 nmol/L or 20 ng/mL) is prevalent in many populations around the globe [16,17]. In an extensive analysis spanning 44 countries, 37.3% of the 195 studies examined reported mean values below 50 nmol/L [18]. By re- gion, mean levels were highest in North America and Europe and lowest in the Middle East and Asia. By age, children (especially newborns [18–20]) and the elderly (especially those institutionalised [18]) generally exhibited the highest risk of low vitamin D levels. Epidemiological studies have also identified that inadequate vitamin D levels are associ- ated with immunopathological conditions including autoimmune diseases, malignancy and inflammatory diseases [21–24]. Of interest to the present review, we [19] and oth- ers [25] have shown that vitamin D deficiency is linked to an increased risk of ALRI in children. Case-control studies from India [26], Turkey [27] and Bangladesh [25] have found that childhood ALRI hospitalisation was associated with low vitamin D levels. In the Bangladesh study [25], the odds of ALRI doubled for each 10 nmol/L decrease in circulat- ing 25-hydroxyvitamin D3 (25(OH)D3). Prospective birth cohort studies in several countries also suggest low cord blood vitamin D is a risk factor for ALRIs. In the Netherlands [28] neonates with 25(OH)D <50 nmol/L (vs >75 nmol/L) had a 6-fold risk of RSV diagnosed ALRI, while in Korea [29] low cord blood 25(OH)D was associated with a 2-fold increased risk of ALRI in the first 6 months of life. Likewise, in northern Australia we discovered that vitamin D deficiency (<50 nmol/L) was common among Aboriginal neonates (44%) and associated with an increased risk of ALRI hospitalisation in the first year of life [19]. While not all studies have found this association, synthesis of data from 12 observational studies [30] suggested that children with 25(OH)D <50nmol/L (vs ≥50 nmol/L) at birth or early infancy had a 3-fold higher risk of ALRI. There is increasing evidence to show that vitamin D exerts broad regulatory effects on the immune response to infection. Indeed, activation of the vitamin D receptor (VDR) by the active metabolite of vitamin D, 1,25 hydroxy-vitamin D3 (1,25(OH)2D3), directly and/or indirectly regulates the expression of up to 5% of all the human genes [31–33]. Many of the target genes are involved in regulating innate immune function such as expression of pattern recognition receptors (PRRs) [34,35] and various cytokines involved in cellular proliferation, differentiation and degradation [36–38]. As vitamin D is intricately linked to innate immune cell function, it is not surprising that deficiency has been associated with inflammatory dysfunction and susceptibility to infection [39–42]. Furthermore, vitamin D supplementation has been shown to decrease the frequency and severity of respiratory infections [43]. Meta-analysis of individual participant data from 25 randomised controlled Nutrients 2021, 13, 276 3 of 24 trials suggests vitamin D supplementation could reduce the risk of ALRI by over 20% if given daily or weekly during a period of deficiency [43,44]. 1.2. Vitamin D Metabolism, Signalling, and Function Humans synthesise the majority (~90%) of their vitamin D in the skin upon expo- sure to sunlight with an ultraviolet (UV) index of 3 or higher with the remainder coming from dietary sources [45] (Figure1). Extreme latitudes, sun avoidance, clothing and deep pigmentation of skin limit epidermal vitamin D production [46], while sunscreens may not limit production as much as previously thought [47]. Cutaneous or dietary sourced vitamin D is hydroxylated in the liver by the enzyme 25-hydroxylase (CYP2R1) to form the major circulating metabolite 25(OH)D3; this metabolite reflects total body stores and is considered the best measure of vitamin D status [48]. The active hormonal vitamin D metabolite, 1,25(OH)2D3, is produced from the circulating 25(OH)D3 stores via a second hydroxylation reaction by 1-α-hydroxylase (CYP27B1) in the kidney or locally, as required by cells of other systems. Production of 1,25(OH)2D3 is tightly regulated by several hor- mones including parathyroid hormone and other catabolic enzymes in its classic endocrine role of calcium/phosphate metabolism and bone homeostasis [46].
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