Vitamin D: Immuno-modulation and tuberculosis treatment.

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Manuscript ID: cjpp-0386

Vitamin D: Immuno-modulation and tuberculosis treatment Paramasivam Selvaraj*, Murugesan Harishankar, Kolloli Afsal

Department of Immunology National Institute for Research in Tuberculosis (Formerly Tuberculosis Research Centre) Indian Council of Medical Research 1, Mayor Sathyamoorthy Road, Chetput Chennai 600 031. INDIA.

*For Correspondence: Dr. P. SELVARAJ Scientist ‘F’ Department of Immunology National Institute for Research in Tuberculosis (Formerly Tuberculosis Research Centre) Indian Council of Medical Research 1, Sathyamoorthy Road Chennai 600 031. INDIA. Phone: 91- 44 - 2836 9761 Fax: +91 - 44 - 2836 2528 E. mail: (i) [email protected] (ii) [email protected]

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Abstract Tuberculosis (TB) is a major global health problem and often coincides with vitamin D deficiency. High doses of vitamin D were widely used to treat TB during pre-antibiotic era. Vitamin D exerts its action through Vitamin D receptor (VDR) and VDR gene polymorphisms are associated with susceptibility or resistance to tuberculosis as well as sputum smear and culture conversion during anti-TB treatment. In vitro studies have revealed that 1,25-dihydroxyvitamin D3 enhances the innate immunity by increased expression of various antimicrobial peptides including cathelicidin and induction of autophagy of the infected cells thus restricts the intracellular growth of Mycobacterium tuberculosis (Mtb) in macrophages. On the other hand, vitamin D has been shown to suppress the pro-inflammatory cytokine response and enhance anti-inflammatory response. Supplementation of vitamin D during anti-TB treatment may be beneficial to minimize the excessive tissue damage during the active stage of tuberculosis disease. Several clinical trials have evaluated vitamin D supplementation as adjunct therapy during anti-TB treatment for tuberculosis. However, results are conflicting due to variations in dose regimens and outcome measures. Further investigations are needed to find out an optimal concentration of vitamin D supplementation along with standard anti-TB drugs to shorten treatment which could be helpful to effectively manage both drug-sensitive and drugresistant tuberculosis. Key words: 1,25-dihydroxyvitamin D3, Vitamin D receptor, antimicrobial peptides, Immunity, clinical trials.

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Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still continues as a major public threat. Results from various epidemiological studies unveil the association between vitamin D deficiency and susceptibility to TB (Wilkinson et al. 2000; Nnoaham and Clarke 2008). During pre-antibiotic era, vitamin D rich source like cod liver oil or sun exposure was employed for the treatment of TB. It has been reported that cod liver oil was used for the treatment of TB and scrofula, a cervical tuberculosis lympadenopathy arising from infection of lymph nodes of the neck by Mtb or related mycobacteria (Guy 1923). The discovery of antibiotics and its wide usage in the treatment of various infectious diseases reformed the conventional treatment and the implication of vitamin D in TB treatment were somewhat ignored. However, higher cost of antibiotics and rise of antibiotic resistance with increasing incidence of multiple drug resistant (MDR) and extremely drug resistant (XDR) TB have encouraged the search of additional therapeutic strategies such as vitamin D supplementation with standard anti-TB treatment. Further, the benefit of vitamin D in TB treatment is gained research interest after demonstrating its role in controlling Mtb proliferation inside the macrophages treated with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] (Rook et al. 1986), provides the first evidence for direct stimulation of innate immunity by 1,25(OH)2D3 during Mtb infection. Moreover, recent studies have shown that 1,25(OH)2D3 induces the production of antimicrobial peptides and autophagy of Mtb infected macrophages thus control the intracellular growth of Mtb (Liu et al. 2006; Yuk et al. 2009).

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Vitamin D metabolism Vitamin D refers to a group of fat-soluble secosteroids comprised of steroid-like proteins: vitamin D2-D7. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are major forms of vitamin D metabolites known for their physiological significance in human. Vitamin D can be obtained from two different sources, either from diet or by ultraviolet B (UVB) rays-mediated synthesis in the epidermal layer of skin. Pre-vitamin D3 synthesis occurs in the skin from 7-dehydroxy-cholesterol by UVB radiation, which is then isomerized to vitamin D3 by thermo-sensitive process. The active form of vitamin D3 evolved through double hydroxylation. The first hydroxylation takes place in the liver into 25-hydroxyvitamin D3 [25(OH)D3] or calcidiol by 25-hydroxylase (De Luca 1974). The 25(OH)D3 is then transported to the kidney and converted into biologically active 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by the second hydroxylation step by 1α-hydroxylase (CYP27B1) (Zehnder et al. 1999). However, the active metabolite 1,25(OH)2D3 triggers the expression of 24-hydroxylase (CYP24), which catabolizes 1,25(OH)2D3 to its inactive metabolite, calcitroic acid thus limits its own activity (Akeno et al. 1997). The bioavailabity of vitamin D metabolites is critical for 1,25(OH)2D3 mediated function. 1,25(OH)2D3 mediated antimicrobial activity depends on the bioavailability of vitamin D3 and inversely related to the levels of vitamin D binding protein (DBP) (Bikle and Gee 1989; Safadi et al. 1999; Chun et al. 2010). Polymorphisms in the DBP are shown to alter its binding affinity for vitamin D and influence the levels of bioavailable vitamin D for many physiological functions (Arnaud and Constans 1993; Powe et al. 2013).

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Vitamin D status and tuberculosis 25-hydroxyvitamin D3 is the principal indicator of vitamin D status in circulation, which has a half-life of approximately 2 weeks. Currently, no international consensus is available on the optimal level for vitamin D. In healthy humans, 25(OH)D3 is present in serum at a concentration of 50–75 nM/L referred as vitamin D adequacy and >75 nM/L or greater represent vitamin D sufficiency. Individuals with 25-50 nM/L of circulating 25(OH)D3 is believed to suffer from vitamin D insufficiency while 350 nM/L) and it is characterised by hypercalcemia, which leads to renal stones and renal failure (Holick 2007). Vitamin D deficiency often found to be associated with susceptibility to tuberculosis. Clinical observational studies reported that in patients with low 25(OH)D3 levels are associated with susceptibility to tuberculosis, increased risk of progression from infection to active disease and poor treatment response (Wilkinson et al. 2000; Sita-Lumsden et al. 2007; Gibney et al. 2008; Nnoaham and Clarke 2008; Sato et al. 2012). An epidemiologic study has shown that TB incidence was two times higher in populations with decreased level of 25(OH)D3 in black population than white population (Stead et al. 1990). It is reported that the risk of progression to active tuberculosis is fivefold higher in household TB contacts with lowest level of 25(OH)D3 (Talat et al. 2010). It has been observed that low levels of 25(OH)D3 are prevalent during winter which may attribute to higher TB incidence during spring and early summer (Martineau et al. 2011a; Nahid et al. 2011; Ralph et al. 2013). 5


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Further, improvement of 25(OH)D3 levels during tuberculosis treatment supported the association between vitamin D deficiency and tuberculosis (Tostmann et al. 2010). Another vitamin D supplementation study in TB patients reported that both lower and higher circulating levels of 25(OH)D3 are associated with progression of active tuberculosis (Nielsen et al. 2010). Vitamin D mechanism of action Vitamin D metabolites are lipophilic in nature and can easily penetrate cell membrane and translocate into the nucleus (Segaert and Bouillon 1998). The biological activity of 1,25(OH)2D3 in target cells is mediated through either cell membrane vitamin D receptor (mVDR) or nuclear VDR (nVDR). 1,25(OH)2D3 binds with mVDR activates intracellular signalling pathways, whereas it regulates the expression of genes and microRNA through binding with nVDR (Wang et al. 2005, 2011; Alvarez-Diaz et al. 2012). Recent studies reported that 1,25(OH)2D3 treatment significantly increased the number of VDR binding sites and altered gene expression in osteoblast cells and human lymphoblastoid cell lines (Meyer et al. 2010; Ramagopalan et al. 2010) and this may vary from cell to cell and depend on time course of 1,25(OH)2D3 exposure (Carlberg et al. 2012). 1,25-dihydroxyvitamin D3 initiates the genomic actions after binding to the nuclear VDR, a member of the nuclear steroid hormone receptor superfamily which also acts as a transcription factor. VDR is comprised of three domains: the N-terminal DNA binding domain (DBD) with two zinc fingers that bind to the grooves of the DNA at vitamin D responsive elements (VDREs), the C-terminal ligand binding domain (LDB) and the hinge region that bind these two domains together. 1,25(OH)2D3 binds to LBD which trigger 6


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heterodimerization of VDR with retinoid X receptor (RXR). This VDR-RXR complex then binds to VDREs and regulates the transcription of target genes. In addition to various genomic actions, vitamin D metabolites also trigger rapid non-genomic actions such as calcium transport, photoprotection of DNA damage due to UV radiation through a membrane-associated rapid response steroid binding protein (MARRS also known as ERp57/GRp58) and VDR (Huhtakangas et al. 2004; Nemere et al. 2004; Sequeira et al. 2012). These studies suggest that vitamin D metabolites can modulate several genomic and non-genomic actions by regulating the panoply of pathways. Vitamin D and innate immunity 1,25-dihydroxyvitamin D3 has been recognized as an important mediator of innate immune functions by enhancing the antimicrobial properties of phagocytes such as neutrophils, monocytes and macrophages. A study has shown the higher activity of 1α-hydroxylase in alveolar macrophages of TB patients (Cadranel et al. 1990). Moreover, another study reported that the activity of 1α-hydroxylase and 1,25(OH)2D3 production are significantly higher in monocytes of TB patients as compared to TB contacts (Tung et al. 2013). 1,25(OH)2D3 induces the differentiation of monocytes into macrophages and enhance the macrophage phagocytosis (Rigby et al. 1984; Xu et al. 1993; Chandra et al. 2004). Further, 1,25(OH)2D3 up regulates the expression of CD14, mannose receptor and DC-SIGN thus augments the phagocytic activity of antigen presenting cells (Oberg et al. 1993; Berer et al. 2000; Piemonti et al. 2000; Estrella et al. 2011). An in vitro study has shown that 1,25(OH)2D3 inhibits the entry as well as survival of Mtb by down regulating the transcription of tryptophan-aspartate-containing coat protein 7


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(TACO) gene in human macrophages (Anand et al. 2008). Moreover, 1,25(OH)2D3 reduces the viability of Mtb by enhancing the fusion of phagosomes and lysosomes in the infected macrophages (Hmama et al. 2004). Vitamin D and antimicrobial peptides 1,25-dihydroxyvitamin D3 induces the transcription of antimicrobial peptides such as β-defensin-2 (DEFB2) and cathelicidin antimicrobial peptide (CAMP). The CAMP gene is then translated into human cathelicidin antimicrobial

peptide

(hCAP18),

which

is

proteolytically

cleaved

by

proteinase-3 into the active form, LL-37 (Sorensen et al. 2001). Earlier study has shown that IFN-γ treatment enhanced the antimicrobial effect of Mtb infected monocytes by upregulating the synthesis of 1,25(OH)2D3 (Rook et al. 1986). It has been shown that TLR2/1 activation by Mtb antigen in macrophages enhanced the VDR and CYP27B1 gene expression that lead to the induction of CAMP (Liu et al. 2006), which restrict the intracellular growth of Mtb (Liu et al. 2007; Martineau et al. 2007a). Further, activation of NADPH oxidase (NOX)2 pathway has been shown to be involved in 1,25(OH)2D3 induced expression of cathelicidin (Yang et al. 2009). Several studies have reported that vitamin D deficiency is correlated with impaired expression of CAMP, which is associated with susceptibility to infectious diseases including tuberculosis (Liu et al. 2006; Jeng et al. 2009; Bhan et al. 2011; Dixon et al. 2012). Recently, another study demonstrated the important role of LL-37, the active form of cathelicidin, which restrict the growth of both drug sensitive and MDR strain of Mtb at the site of infection (Rivas-Santiago et al. 2013).

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1,25(OH)D3 was also shown to influence the host defence against mycobacterial infection through the activation of autophagy mechnanism, which degrade the cell’s own components through the lysosomal machinery (Jo 2010). Studies have reported that vitamin D-induced expression of hCAP18 trigger autophagy of infected cells and play a crucial role in the elimination of intracellular Mtb (Yuk et al. 2009; Shin et al. 2011). It has been shown that vitamin D supplementation under in vitro condition restored the IFN-γ mediated antimicrobial peptide expression, phagosome-lysosome fusion and autophagy induction in Mtb infected macrophages (Fabri et al. 2011). In addition to cathelicidin, 1,25(OH)2D3 is also shown to up regulate the expression of other antimicrobial peptides such as DEFB2, which play a crucial role in the intracellular killing of mycobacteria (Wang et al. 2005; Liu et al. 2006). It has been reported that increased intracellular concentration of iron favours the survival and growth of Mtb in macrophages (Sow et al. 2007, 2009). A recent study has shown that 1,25(OH)2D3 down regulates the expression of hepcidin antibacterial protein (HAMP), which is involved in the intracellular transport of iron (Bacchetta et al. 2013). This decreased intracellular concentration of iron may suppress the survival of intracellular bacteria such as Mtb. These studies suggest that an adequate vitamin D level is required for eliciting optimum antimicrobial response against Mtb infection. Vitamin D and inflammation Matrix metalloproteinase (MMP) is a collagenase which can degrade the pulmonary extracellular matrix and implicated in the pulmonary cavitation observed in TB patients. 1,25(OH)2D3 treatment of peripheral blood mononuclear cells is shown to attenuate the Mtb-induced expression of matrix 9


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metalloproteinases (MMPs) such as MMP-7, MMP-9 and MMP-10 (Anand and Selvaraj 2009; Coussens et al. 2009). In addition, 1,25(OH)2D3 has been shown to suppress exacerbated inflammatory responses by down regulating the expression of TLR2 and TLR4 on monocytes, which prevent excessive TLR activation during infection (Sadeghi et al. 2006; Khoo et al. 2011). Vitamin D and antigen presentation 1,25(OH)2D3 also modulates the immune responses by influencing the antigen presentation by macrophages and dentritic cells (DCs). DCs share the same cell lineage as monocytes and macrophages and show similar patterns of VDR and CYP27B1 expression. 1,25(OH)2D3 is shown to inhibit antigen presentation by reducing the expression of class II major histocompatibility complex (MHC) and other co-stimulatory molecules in macrophages and DCs (Xu et al. 1993; Berer et al. 2000; Griffin et al. 2000; Gauzzi et al. 2005; Pedersen et al. 2009). 1,25(OH)2D3 also suppresses DC differentiation and maturation by down regulating the transcription of relB gene, which impairs NF-κB signalling (Dong et al. 2003, 2005). During maturation, DCs express CYP27B1 abundantly and 1,25(OH)2D3 produced by mature DCs might play an important role in generating tolerogenic immune response by suppressing the maturation of immature DCs in a paracrine fashion (Hewison et al. 2003). However, it has been reported that 1,25(OH)2D3 enhances the mycobacterial antigen presentation by monocytes and this ability of monocytes is higher in frequent TB contacts than active TB and healed TB patients (Tung et al. 2013).

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Vitamin D and adaptive immunity Although the innate immunity is important for bacterial killing, the ability of a host to contain and eradicate pathogens such as Mtb also requires the adaptive or acquired immunity. Expression of VDR as well as vitamin Dactivating enzymes has been shown in activated T and B cells (Bhalla et al. 1983; Provvedini et al. 1983). VDR expression by these cells is very low in resting conditions, but its expression is upregulated significantly upon activation and proliferation of both T and B cells. It has been shown that 1,25(OH)2D3 suppresses T-cell proliferation by blocking the transition from early G1 phase to late G1 phase (Bhalla et al. 1984; Nunn et al. 1986) and inhibiting the expression of c-myc mRNA (Karmali et al. 1991). Our previous study reported that 1,25(OH)2D3 while it enhances the spontaneous lymphoproliferative response, it suppresses mycobacterial antigen-induced lymphocyte response in normal healthy subjects (Chandra et al. 2004). The balance between inflammatory and anti-inflammatory response is a critical factor in TB susceptibility and a shift towards aggressive proinflamatory or too much anti-inflammatory cytokine response may lead to poor bacterial control and development of active disease (Lin and Flynn 2010). The 1,25(OH)2D3 modulated immune response is best characterized for Th1 cells, where it regulates T cell proliferation and cytokine production. It has been shown that 1,25(OH)2D3 suppressed the Th1 response by down regulating the production of proinflammatory cytokines such as IFN-γ, IL-6, IL-12 and TNF-α and chemokines (Lemire et al. 1985; Muller et al. 1993; Lemire et al. 1995; Vidyarani et al. 2007; Prabhu Anand et al. 2009; Khoo et al. 2011; Selvaraj et al. 2012), whereas it enhances the development of Th2 cells and augment the 11


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production of anti-inflammatory cytokines TGF-β1, IL-4 and IL-10 (Boonstra et al. 2001; Deluca and Cantorna 2001; Coussens et al. 2009). It is reported that vitamin D supplementation limits the inflammatory response by suppressing Mtb antigen induced proinflammatory cytokine response and accelerated the sputum smear conversion during anti-tuberculosis treatment (Coussens et al. 2012). It has been shown that neutralization of TNF-α using anti-TNF-α antibody during anti TB treatment leads to disruption of granuloma integrity, which augmented the bacterial clearance and reduced lung pathology (Bourigault et al. 2013). Moreover, recent studies revealed that 1,25(OH)2D3 down regulates the expression of Th17-derived cytokines such as IL-17 and IL-21 and regulates Th17 cells mediated immune functions (Jeffery et al. 2009; Tang et al. 2009; Colin et al. 2010; Joshi et al. 2011). Vitamin D also exerts its suppressive effect by upregulating the differentiation of IL-10secreting CD4+CD25+ T-regulatory cells (Treg) in vitro (Barrat et al. 2002; Penna et al. 2005, 2007; Baeke et al. 2011). Clinical trial studies reported that high doses of vitamin D3 supplementation increases the frequency of Treg cells (Prietl et al. 2010; Bock et al. 2011). Different mechanisms are proposed for the inhibitory action of 1,25(OH)2D3 on pro-inflammatory cytokine production. It has been shown that 1,25(OH)2D3 down regulates NF-κB signalling pathways by inhibiting RelB protein expression and enhances production of IκBα, which reduces the nuclear translocation of NF-κB (Song et al. 2013) and leads to decreased production of pro-inflammatory cytokines. Since vitamin D downregulates the Th1 and Th17 proinflammatory response, vitamin D supplementation during anti-TB treatment could be beneficial to

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suppress and regulate the excessive inflammatory response in active tuberculosis disease. In addition, 1,25(OH)2D3 may exert differential effects on resting and activated B cells. B cells constitutively express VDR and their expression is up regulated upon activation (Morgan et al. 2000). It has been shown that 1,25(OH)2D3 inhibits the proliferation of activated B cells, generation of plasma cells, class-switched memory cells and in the reduction of immunoglobulin production (Chen et al. 2007). Another study has shown that 1,25(OH)2D3 inhibits the IgE production whereas it upregulates IL-10 expression in B cells and thus play an important role in the allergic immune response (Heine et al. 2008). Over all, vitamin D3 while enhances the innate immunity by enhancing the antimicrobial activity to restrict the intracellular Mtb growth in monocytes/macrophages, it down regulates the T-cell mediated inflammatory response which may help to limit the excessive tissue damage at the site of infection. Vitamin D Receptor gene polymorphisms and tuberculosis Human VDR gene located on chromosome 12q is polymorphic and numerous single nucleotide polymorphisms have been described. Three adjacent 3′ untranslated region polymorphisms such as BsmΙ, ApaΙ and TaqΙ are the most frequently studied VDR gene polymorphisms that can affect the mRNA stability and protein translation efficiency. The other commonly occurring polymorphism is FokΙ at the translation initiation sites in exon 2. The two promoter polymorphisms Cdx-2 and A1012G have been identified in the

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VDR gene which may involve in regulation of mRNA expression. The Cdx-2 promoter polymorphism (G/A) in Cdx (Caudal-Related homeodomain protein) binding site is suggested to play an important role in vitamin D regulated calcium absorption (Arai et al. 2001). Another polymorphism A1012G is located upstream of transcription start site 1-a promoter region. The A allele of A1012G polymorphism allows binding of GATA-3, a transcription factor, which induce polarization of immature T cells to Th2 cells (Halsall et al. 2004). Another study reported that TaqΙ T allele is associated with decreased production of tissue inhibitor of metalloproteinase-1 (TIMP-1), which is an inhibitor of MMP-9 and lower production of TIMP-1 is correlated with the severity of TB (Dean et al. 1996; Timms et al. 2002). Association of VDR gene polymorphisms with susceptibility or protection to TB has been shown (Gao et al. 2010; Chen et al. 2013). Vitamin D Receptor gene polymorphisms and TB treatment outcome Vitamin D receptor gene polymorphisms have been associated with sputum smear and culture conversion time during anti-TB treatment. In a Peruvian community with a high incidence of tuberculosis, the conversions were significantly faster among participants with the FokΙ FF genotype and TaqΙ Tt genotype (Roth et al. 2004). Another similar study reported that ApaΙ AA and TaqΙ TT and Tt containing genotypes were predictive of a faster response to treatment. This study suggested that the time taken for an individual to convert to sputum negativity while on anti-TB therapy can be predicted independently by the VDR genotypes (Babb et al. 2007). Recently, improved sputum conversion has been shown in TB patients treated with vitamin D in patients with TaqΙ ‘tt’ genotype (Martineau et al. 2011b). In a 14


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cross-sectional study carried out in north Indian population reported that the TaqΙ t allele and low serum level of 25(OH)D is associated with the development of multidrug resistant - TB and delayed smear conversion time to treatment (Rathored et al. 2012). Vitamin D and tuberculosis treatment Hippocrates, the father of medicine, apparently used heliotherapy (exposure to sunlight) to treat phthisis (tuberculosis) (Masten 1935). In 1650, Francis Glisson recognized rickets in children and began the discovery of vitamin D. In 1822, Sniadecki reported the association between rickets and lack of sunlight exposure (Sniadecki -cited by Mozolowski 1939). Finsen successfully treated lupus vulgaris, a cutaneous TB using the ultraviolet (UV) radiation and he was awarded the Nobel Prize for Medicine in 1903. In 1930s, vitamin D3 which is isolated from cod liver oil was widely used in tuberculosis treatment and prevention until the discovery of antibiotics. During the preantibiotic era, high doses of vitamin D were widely used to treat active tuberculosis. Charpy used 600,000 international units (IU) of vitamin D2 to treat cutaneous tuberculosis (Charpy and Dowling 1947). Williams reported the beneficial effect of cod liver oil in the treatment of TB as well as the importance of sunlight has been observed in TB treatment (Williams 1849). It has been reported that UV light B exposure is sufficient to double the circulating 25(OH)D3 levels, but no significant change in antimycobacterial immunity was observed (Yesudian et al. 2008).

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Vitamin D supplementation in clinical trials Vitamin D deficiency has been identified as one of the risk factor in the development of TB. Several clinical trials were conducted to find out the effect of vitamin D supplementation in TB prevention and for the shortening of TB treatment. Randomized controlled trials investigated the effects of adjunctive vitamin D in patients with TB. In 1969, Brincourt reported that oral supplementation with 15 mg (600,000 IU) of vitamin D2 supplements were able to dissolve cavities in TB patients (Brincourt 1969). Another study was carried out with 125 µg of vitamin D2 supplementation to find out the effect of vitamin D on serum calcium concentration in TB patients and no hypercalcaemia was observed in those patients (Gwinup et al. 1981). However, occurrence of hypercalcaemia has been reported in nineteen out of thirty TB patients receiving daily doses of 10–95 µg vitamin D and a daily dose of 60 µg vitamin D elevated the mean serum calcium level in healthy controls (Narang et al. 1984). In contrary, hypercalcaemia was not observed in other studies carried out with higher doses of vitamin D supplementation (Stern et al. 1981; Tjellesen et al. 1986). Morcos et al investigated the effects of 25µg vitamin D as a daily supplement on twenty-four children in Egypt receiving antimicrobial therapy for TB and showed more apparent clinical and radiographic improvement (Morcos et al. 1998). A study carried out in Tanzania revealed that multivitamin supplement including vitamin D in a randomized clinical trial has reported 50% reduction in mortality among human immunodeficiency virus infected patients with TB (Range et al. 2006). Moreover, daily dose of 250 µg vitamin D in sixty-seven pulmonary TB patients in Indonesia resulted in more 16


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rapid sputum clearance of acid-fast bacilli and radiological improvement at 6 weeks after initiation of antimicrobial therapy (Nursyam et al. 2006). A doubleblinded randomized controlled trial was conducted in 192 healthy adult TB contacts and was supplemented with a single oral dose of vitamin D 2.5 mg or placebo. A functional whole blood assay was performed after 6 weeks to assess the growth of recombinant reporter mycobacteria in vitro using BCGlux assay and IFN-γ production to Mtb antigens were also determined. The results revealed that vitamin D supplementation significantly enhanced the ability of participant’s whole blood to restrict the growth of reporter mycobacteria but did not affect antigen stimulated IFN-γ secretion (Martineau et al. 2007b). In contrast, another double blind placebo-controlled trial concluded that three doses of 100,000 IU/2.5mg vitamin D3 supplementation had no effect on clinical outcome or mortality amongst TB patients in Guinea– Bissau (Wejse et al. 2009). A study conducted in multiethnic cohort of TB patients in UK using a single oral dose of 2.5 mg vitamin D2 corrected for hypovitaminosis D at 1 week post dose induced a 109.5 nmol/l mean increase in their serum 25(OH)D3 concentration. Hypercalcemia was not found in patients receiving vitamin D2 (Martineau et al. 2009). In a case-control study conducted in Greenland reported that vitamin D supplementation could be beneficial to vitamin D deficient TB patients that reduced the number of TB cases to 29% whereas the vitamin D supplementation increased the risk of TB in patient with sufficient or high vitamin D levels (Nielson et al. 2010). Studies have been carried out to understand the effect of nutritional supplementation of vitamins and minerals and the outcome in tuberculosis patients. A randomized

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trial conducted in India reported that vitamins and minerals rich food supplementation enhanced the treatment response and higher sputum convertion rate in 100 patients who were started with anti-TB therapy (Jahnavi and Sudha 2010). In contrast, a pilot randomized study reported that multivitamin supplementation has no improvement in 103 patients receiving anti-tuberculosis drugs (Sudarsanam et al. 2011). A study conducted in UK using four doses of 100,000 IU/25 mg vitamin D3 was found successful in elevating the serum 25(OH)D3 level in 146 patients with smear positive TB, but showed no overall difference in sputum conversion time between treatment and placebo groups (Martineau et al. 2011b). Another study conducted in 120 latent TB infected Mongol school children revealed that supplementation with 800 IU vitamin D per day for six months significantly enhanced the 25(OH)D levels and also 59% reduction in the tuberculin skin test conversion rate (Ganmaa et al. 2012). In a randomized controlled trail, adjunctive high dose of 2.5mg oral vitamin D supplementation enhanced the sputum smear conversion and accelerated the resolution of inflammatory responses in 95 patients receiving antimicrobial therapy for pulmonary tuberculosis (Coussens et al. 2012). In a recent study, 600,000 IU of intramuscular supplementation of vitamin D3 or placebo was given to 259 patients with pulmonary tuberculosis. The IFN-γ secretion was studied in Mtb antigen induced whole blood cells of PTB patients at ‘0’ and 12th week. Vitamin D administration for 12 weeks accelerated the clinical and radiographic improvement in all the TB patients and enhances the host immune activation by increased IFN-γ secretion (Salahuddin et al. 2013). These studies suggested that the optimum level of vitamin D could enhance

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the innate immunity and thus play an important role in the prevention of tuberculosis. Conclusions Vitamin D in the form of cod liver oil and sun light exposure was used to treat tuberculosis during pre-antibiotic era. Eventhough the discovery of antibiotics decline the usage of vitamin D in the treatment of TB, the immunomodulatory effect of vitamin D gained more research interest as it enhances the antimicrobial peptide expression and restrict the intracellular growth of Mtb. Studies have demonstrated the association of VDR gene variants on sputum conversion time during anti-TB treatment. Further, the effect of vitamin D on the sputum conversion time may also be altered by differential expression of VDR. Epidemiological studies have revealed that susceptibility to tuberculosis is associated with vitamin D deficiency. In several clinical trials, vitamin D is used as an adjunct supplementation in TB treatment. Some of the studies revealed better treatment response, while other studies reported conflicting results. It has been suggested that well designed studies with large sample size are needed to optimize vitamin D supplementation during anti-TB treatment which could be helpful to prevent excessive inflammatory response and faster recovery from the disease. Acknowledgements We acknowledge the Indian Council of Medical Research, New Delhi, for providing senior research fellowship to Mr. K. Afsal.

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Vitamin D and the immunomodulation of rotator cuff injury.

Vitamin D and tuberculosis: more effective in prevention than treatment?

Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia: a prospective clinical study.

Immunomodulation in human and experimental arthritis: including vitamin D, helminths and heat-shock proteins.

Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study.

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis: risk factors and treatment outcomes.

Tuberculosis and vitamin D: what's the rest of the story?

Vitamin D and tuberculosis: a multicenter study in children.

Vitamin D and tuberculosis: a review on a hot topic.

Prolonged treatment with vitamin D.

Vitamin D deficient states. Pathophysiology and treatment.

Change in serum CXCL10 levels during anti-tuberculosis treatment depends on vitamin D status [Short Communication].

Vitamin D status and incidence of tuberculosis among contacts of pulmonary tuberculosis patients.

Calcitriol treatment in vitamin D-dependent and vitamin D-resistant rickets.

Epilepsy treatment by sacrificing vitamin D.

Serum sclerostin is decreased following vitamin D treatment in young vitamin D-deficient female adults.

Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis.

Expression of vitamin D receptor and vitamin D status in patients with oral neoplasms and effect of vitamin D supplementation on quality of life in advanced cancer treatment.

Vitamin D, Vitamin D Receptor, and Tissue Barriers.

Vitamin d binding protein and vitamin d levels.

Vitamin D receptor and vitamin D action in muscle.

Vitamin D, vitamin D analogs (deltanoids) and prostate cancer.

[Tuberculosis: plasma levels of vitamin D and its relation with infection and disease].

Vitamin D and falls.