Review Article Open Access
Vitamin Deficiency and Tuberculosis: Need for Urgent Clinical Trial for Managment of Tuberculosis
Surajit Chakraborty1, Kirtiman Syal2, Rajasri Bhattacharyya3 and Dibyajyoti Banerjee1*
1Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh-160012, India
2Department of Biophysics, Indian Institute of Science, Bangalore, India
3Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala, India
2Department of Biophysics, Indian Institute of Science, Bangalore, India
3Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala, India
*Corresponding author: Dibyajyoti Banerjee© Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh-160012, India, Tel: 91-172-2755232; Fax: 91-172-2744401; E-mail:
Received: March 07, 2014; Accepted: April 07, 2014; Published: April 09, 2014
Citation: Chakraborty S, Syal K, Bhattacharyya R, Banerjee D (2014) Vitamin Deficiency and Tuberculosis: Need for Urgent Clinical Trial for Managment of Tuberculosis. J Nutrition Health Food Sci 2(2): 1-6.  http://dx.doi.org/10.15226/jnhfs.2014.00118
The scenario of tuberculosis is getting complicated due to the emergence of multiple drug resistant and extensively drug resistant strains. The advent of BCG vaccination is understood to be a failure as far as primary prevention of the disease. In this context, there is a considerable current interest of development of host based chemotherapies for management of the disease. Since malnutrition is a recognized associate of tuberculosis from times immemorial the role of vitamin deficiency is reviewed keeping in view the molecular pathogenesis of the disease. Considering the recent evidences relevant to the subject, we have concluded that there is an urgent need for clinical trial of several vitamins for the management of tuberculosis.
Keywords: Tuberculosis; Vitamin; Malnutrition; Antioxidant; Neuropathy
Tuberculosis is one of the deadliest bacterial killers affecting almost all corners of the globe. In-spite of the discovery of antitubercular antibiotics and an available vaccine (BCG vaccine) against Mycobacterium tuberculosis we are unable to tackle the occurrence of tuberculosis. Moreover the increasing prevalence of HIV-AIDS and diabetes mellitus is being proved to be providing predisposition to tuberculosis (Global tuberculosis control–surveillance, planning, financing [1-5]. As witnessed by the WHO, which has estimated that, in the year 2012, 8.6 million people have developed tuberculosis and 1.3 million have died of the disease, including 320000 deaths of HIV-TB co-infected people . Long term multiple antibiotic therapy, which is associated with many adverse drug related events have diminished patient compliance with the anti-tubercular chemotherapy. This fact, in turn, has raised the new, deadlier MDR-TB and XDR-TB strains [7-9]. The whole scenario of current day tuberculosis is a matter of panic. It questions the effectiveness of anti-tubercular antibiotics, immunologic efficacy of century old BCG vaccine and all other medical advents present at the moment to combat tuberculosis.
Malnutrition has always been recognized to be a very important predisposing factor for all infectious diseases including tuberculosis [10-12]. Vitamin deficiency and malnutrition are the biggest challenges in the developing nations where the disease burden of tuberculosis is noticeably very high. Vitamins are bio-molecules that maintain body’s physiology and boost the protective immune system. Vitamins are responsible for a spectrum of vital functions in the body due to their anti-oxidant, pro-oxidant, anti-inflammatory effects and metabolic functions [13-17]. The anti-oxidant system of the human body is largely contributed by anti-oxidant vitamins (vitamin-E, C, A). The anti-tubercular effects of vitamins are also being studied since the pre-streptomycin age, but till today systematic clinical trial of vitamin supplementation is lacking in the scenario of tuberculosis. It is in this context, we have reviewed the role of major vitamins in the background of tuberculosis.
Vitamin A metabolites are essential for normal growth and development. This boosts up both body’s natural innate immunity as well as the adaptive immunity [18-23]. Retinoic acid, a vitamin-A metabolite has been shown to inhibit expression of toll like receptor-II (TLR-II) on the cellular surface and thus affect the TLR-II signalling pathway and prevents Mycobacterium tuberculosis and other gram positive bacteria cause human infections [20,24-31]. It also increases the phagocytic activity of human macrophages . Importantly, a recent study has found that retinoic acid alone or with iron can reduce the transferring receptors up to a significant level in promonocytic cell line U937 . This might lead to a restriction in the availability and accessibility of iron in the intracellular environment. Iron is essentially needed by Mycobacterium tuberculosis for almost all of its strategies for successful intracellular survival and pathogenecity in human hosts, including the activity of enzymes against oxidative burst, supply of oxygen to hypoxic atmosphere by mycobacterial truncated haemoglobins, arresting phagosome-lysosome fusion and acidification in an iron dependant manner, host cell cholesterol utilization etc [34-64]. Moreover, this retinoic acid (vitamin A) along with vitamin D3 or with hepatic chenodeoxycholic acid can reduce the synthesis tryptophan aspartate coating protein (TACO) by down regulation of TACO gene expression at the transcriptional level [65,66]. TACO protein is believed to be very essential for the mycobacterial entry and successful intra-phagosomal survival in the macrophages as it inhibits the phagosome maturation i.e., the phagosome-lysosome fusion and acidification and thus contribute in the pathogenecity and virulence of Mycobacterium tuberculosis [67,68]. Vitamin A helps in the normal function of immune cells and also enhances the synthesis of iNOS and other essential cytokines with antitubercular activity [69-77]. Moreover, oral administration of retinoic acid can reduce mycobacterial growth in vivo and physiological and pharmacological doses of retinoic acid in pre and post infectious conditions show preventive and therapeutic effects respectively [74,78]. So, deficiency in dietary vitamin-A can hamper the activity of both innate and adaptive immunity while supplementation can boost the body’s fight against Mycobacterium tuberculosis along with the administration of anti-tubercular drug regimens.
Though the direct association between tuberculosis and vitamin-B deficiency is not known, but vitamin-B supplementation is well recommended in order to avert several neurological complications in tuberculosis patients. Administration of pyrazinamide, isoniazid while treating tuberculosis commonly causes vitamin-B6 deficiency in the body which in turn gives rise to different peripheral neuropathies [79,80]. It is also reported that vitamin-B12 deficiency is a cause of neuropathy in patients with ileal tuberculosis .
Vitamin-C is well known for its anti-oxidant and pro-oxidant actions [82-83].As an immunological maintenance measure vitamin-C can enhance the function of the immune system in different ways like T-lymphocyte proliferation etc. and thus strengthens the cell mediated immunity [84-88]. Both lower dietary intake and lower blood concentration of vitamin-C are considered to be associated with the higher incidence of tuberculosis [89,90]. In patients with active cavitary tuberculosis, the anti-oxidant vitamin-C level gets substantially decreased with an increase in lipid peroxides [91-93]. Vitamin-C can halt spreading of infections including tuberculosis. It also accelerates recovery from tuberculosis by healing decay cavity and turns sputum acid fast bacillus (AFB) negative . Most interestingly in a recent study, vitamin-C has been shown to have an extraordinary capability of killing of drug susceptible, multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis, which strongly suggest and support the incorporation of vitamin-C and iron (needed for its strong mycobactericidal action) supplementation along with the anti-tubercular antibiotic therapy . Paradoxically, it is believed that the blind exogenous administration of antioxidants may augment the mycobacterial antioxidant system to protect itself in patient suffering from tuberculosis, but experimental supports are there which show that an adequate dietary supplementation of vitamin-C contributes protection against tuberculosis and lowers the incidents [94,96-98]. Adequate anti-oxidant vitamin supplementation along with standard anti-tubercular antibiotic regimen has been demonstrated to accelerate healing of tuberculosis .
Vitamin D is well known for its pivotal role in bone mineral density (BMD) and calcium homeostasis in the body . Vitamin D deficiency and its association with tuberculosis is very well known from the pre-antibiotic era as in those days exposure to sunlight and vitamin D supplementation (cod liver oil) were the most reliable treatment choice for treating tuberculosis [100-101].
It is believed that vitamin-D deficiency is associated with increased infection of the upper respiratory tract . Till date, a large number of studies have proven the association between vitamin D deficiency and the occurrence of tuberculosis [102-107]. Vitamin D receptors (VDR) are found to be present on different immune cell surfaces including T and B cells suggest that, they need vitamin-D for performing the cellular functions . Vitamin D has been shown to increase the phagocytic activity of macrophages. Monocytes incubated with cholecalciferol (vitamin-D3) metabolites have been shown to induce anti-tubercular activity . Moreover, it enhances the production of the body’s antimicrobial/antimycobacterial peptide LL-37, a member of the cathelicidin peptide family [109-111]. Vitamin-D also enhances the fusion of phagosome and lysosome, a very significant step towards the elimination of intra-phagosomal Mycobacterium tuberculosis from the human body [110,112]. Vitamin-D deficiency has been recognized as a major risk factor for tuberculosis as low serum vitamin-D found to be associated with the development of active tuberculosis. Hypovitaminosis D is also found as a common feature in HIV positive patients and maybe that’s why the most common opportunistic infection in these people is tuberculosis [113,114]. Vitamin-D supplementation in this HIV-TB co-infected patient population has shown some amazing hope with sputum clearance and radiological improvement which in turn caused an appreciable reduction in mortality .
Several studies have reported substantial reduction of anti-oxidant vitamin-E in patients suffering from tuberculosis. Alpha tocopherol (vitamin-E) is as capable as ascorbic acid (Vitamin-C) in cavity healing in active cavitary tuberculosis and thus having an accelerating role in healing tuberculosis [94,116].
Vitamin-K has vital functions in the formation of coagulation factors by the liver. Hepatotoxic anti-tubercular drug (e.g.; Pyrazinamide, Isoniazid, Rifampicin) induced hepatotoxicity may hamper the blood coagulation physiology e.g., cerebral hemorrhage is reported due to vitamin-K deficiency in patients suffering from congenital tuberculosis .
Pre-infective routine dietary nutrition with essential vitamins and minerals has effective preventive capability against the occurrence of disease tuberculosis. Multivitamin supplementation along with anti-tubercular antibiotic therapy is very much needful as it provides anti-tubercular capability to the body, accelerates healing of Mycobacterium tuberculosis caused cavity and ulcer, reduces anti-tubercular drug induced adverse effects and helps the body reclaiming normal physiological function of affected organs. Dietary vitamin supplementation as a measure of nutritional up gradation will definitely help in effective tuberculosis treatment and also low down the prevalence of tuberculosis especially in the countries with higher disease burden. However, blind supply of antioxidant vitamins may also be harmful. Therefore, we feel systematic clinical trials should be conducted focusing on the above area to construct a combination regime of vitamin supplementation that can combat tuberculosis.
- World Health Organization (WHO) (2006) Global tuberculosis control–surveillance, planning, financing.WHO Report 2006, Geneva.
- Chaisson RE, Martinson NA (2008) Tuberculosis in Africa combating an HIV driven crisis. The New England Journal of Medicine 358 (11): 1089–92.
- Restrepo BI (2007) Convergence of the tuberculosis and diabetes epidemics: renewal of old acquaintances. Clin Infect Dis 45 (4): 436–438.
- Bhattacharyya R, Banerjee D (2011) Glycation of calmodulin binding domain of iNOS may increase the chance of occurrence of tuberculosis in chronic diabetic state. Bioinformation 7(7): 324–327.
- Satyanarayana S, Kumar AMV, Wilson N, Kapur A, Harries, et al. (2013) Taking on the diabetes tuberculosis epidemic in India paving the way through operational research. Public Health Action 3(1):1-2(2).
- World Health Organization (WHO) (2013) Global tuberculosis report 2013, Geneva.
- JAIN A, DIXIT P (2008) Multidrug resistant to extensively drug resistant tuberculosis: What is next? J Biosci 33(4): 605–616.
- SALIH MA, MERZA AM(2010) RISK FACTORS FOR MULTI-DRUG RESISTANT TUBERCULOSIS: A REVIEW. Duhok Med J 4(2): 1-7.
- Field SK, Fisher D, Jarand JM, Cowie RL. (2012) New Treatment Options for Multidrug-Resistant Tuberculosis. Ther Adv Resp Dis 6(5): 255-268.
- Kumar V, Abbas AK, FaustoN, Mitchell RN (2007) Robbins Basic Pathology. (8th edn), Saunders Elsevier. Philadelphia, USA, pp.516–522.
- Lawn SD, Zumla AI (2011) "Tuberculosis". Lancet 378 (9785): 57–72.
- Hood MLH (2013) A narrative review of recent progress in understanding the relationship between tuberculosis and protein energy malnutrition. Eur J Clin Nutr 67(11): 1122–1128.
- CARR A, FREI B (1999) Does vitamin C act as a pro-oxidant under physiological conditions? The FASEB Journal 13(9): 1007-1024.
- Brambilla D, Mancuso C, Scuderi MR, Bosco P, Cantarella G, Lempereur L, et al. (2008) The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile. Nutrition Journal 7:29.
- Bouayed J, BohnT (2010) Exogenous antioxidants - Double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses: Oxid Med Cell Longev 3(4): 228-237.
- Ciccone MM, Cortese F, Gesualdo M, Carbonara S, Zito A, et al. (2013) Dietary Intake of Carotenoids and Their Antioxidant and Anti-Inflammatory Effects in Cardiovascular Care. Mediators of Inflammation 2013.
- Wahlqvist ML (2013) Antioxidant relevance to human health. Asia Pac J Clin Nutr 22(2): 171-176.
- Iwata M, Eshima Y, Kagechika H (2003) Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol 15(8): 1017-1025.
- Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY , et al.(2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21(4):527-538.
- Ma Y, Chen Q, Ross AC (2005) Retinoic acid and polyriboinosinic:polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations. J Immunol 174(12): 7961-7969.
- Ma Y, Ross AC (2005) The anti-tetanus immune response of neonatal mice is augmented by retinoic acid combined with polyriboinosinic:polyribocytidylic acid. Proc Natl Acad Sci U S A 102(38): 13556-13561.
- Villamor E, Fawzi WW (2005) Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev 18(3): 446-464.
- Ott F, Bollag W, Geiger JM (1996) Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy. Dermatology 193(2): 124-126.
- Abel B, Thieblemont N, Quesniaux VJ, Brown N, Mpagi J, Miyake K, et al. (2002) Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol 169(6): 3155-3162.
- Branger J, Leemans JC, Florquin S, Weijer S, Speelman P,Van Der Poll T (2004) Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice. Int Immunol 16(3): 509-516.
- Liu PT, Krutzik SR, Kim J, Modlin RL (2005) Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and function. J Immunol 174(5): 2467-2470.
- Tenaud I, Khammari A, Dreno B (2007) In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions. Exp Dermatol 16(6): 500-506.
- Jalian HR, Liu PT, Kanchanapoomi M, Phan JN, Legaspi A, et al. (2008) All-trans retinoic acid shifts Propionibacterium acnes-induced matrix degradation expression profile toward matrix preservation in human monocytes. J Invest Dermatol 128(12): 2777-2782.
- Harding CV, Boom WH (2010) Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol 8(4): 296-307.
- Juarez E1, Nunez C, Sada E, Ellner JJ, Schwander SK, et al. (2010) Differential expression of Toll-like receptors on human alveolar macrophages and autologous peripheral monocytes. Respir Res 11:2.
- Valins W, Amini S, Berman B (2010) The Expression of Toll-like Receptors in Dermatological Diseases and the Therapeutic Effect of Current and Newer Topical Toll-like Receptor Modulators. J Clin Aesthet Dermatol 3(9): 20-29.
- Chen Q, Ross AC (2004) Retinoic acid regulates cell cycle progression and cell differentiation in human monocytic THP-1 cells. Exp Cell Res 297(1): 68-81.
- Iturralde M, Vass JK, Oria R, Brock JH (1992) Effect of iron and retinoic acid on the control of transferrin receptor and ferritin in the human promonocytic cell line U937. Biochim Biophys Acta 1133(3):241-246.
- Edwards KM, Cynamon MH, Voladri RK, Hager CC, DeStefano MS, et al. (2001) Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis. Am J Respir Crit Care Med 164(12): 2213-2219.
- Fang FC, DeGroote MA, Foster JW, Baumler AJ, Ochsner U, et al. (1999) Virulent Salmonella typhimurium has two periplasmic Cu, Zn-superoxide dismutases. Proc Natl Acad USA 96(13): 7502-7507.
- Igwe EI, Rüssmann H, Roggenkamp A, Noll A, Autenrieth IB, et al. (1999) Rational live oral carrier vaccine design by mutating virulence-associated genes of Yersinia enterocolitica. Infect Immun, 67(10):5500-5507.
- Piddington DL, Fang FC, Laessig T, Cooper AM, Orme IM, et al. (2001) Cu,Zn superoxide dismutase of Mycobacterium tuberculosis contributes to survival in activated macrophages that are generating an oxidative burst. Infect Immun 69(8): 4980-4987.
- Zhang Y, Lathigra R, Garbe T, Catty D, Young D (1991) Genetic analysis of superoxide dismutase, the 23 kilodalton antigen of Mycobacterium tuberculosis. Mol Microbiol 5(2): 381-391.
- Dussurget O, Stewert, G, Neyrolles O, Pescher, P, Young D, et al. (2001) Role of Mycobacterium tuberculosis copper-zinc superoxide dismutase. Infect Immun 69(1): 529-533.
- Harth G, Horwitz MA (1999) Export of recombinant Mycobacterium tuberculosis superoxide dismutase is dependent upon both information in the protein and mycobacterial export machinery. A model for studying export of leaderless proteins by pathogenic mycobacteria. J Biol Chem 274(7): 4281-4292.
- Wu CH, Tsai-Wu JJ, Huang YT, Lin CY, Lioua GG, et al. (1998) Identification and subcellular localization of a novel Cu, Zn superoxide dismutase of Mycobacterium tuberculosis. FEBS Lett 439(1-2): 192-196.
- Rodriguez GM, Voskuil MI, Gold B, Schoolnik GK, Smith I (2002) ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun 70(7): 3371-3381.
- Meena LS, Rajni (2010) Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J 277(11): 2416-2427.
- Yu S, Chouchane S, Magliozzo RS (2002) Characterization of the W321F mutant of Mycobacterium tuberculosis catalase-peroxidase KatG. Protein Sci 11(1): 58-64.
- Netto LES, Chae HZ, Kang SW, Rhee SG, Stadtman ER (1996) Removal of hydrogen peroxide by thiol-specific antioxidant enzyme (TSA) is involved with its antioxidant properties. TSA possesses thiol peroxidase activity. J Biol Chem 271(26): 15315-15321.
- Rho BS, Hung LW, Holton JM, Vigil D, Kim SI, et al. (2006) Functional and structural characterization of a thiol peroxidase from Mycobacterium tuberculosis. J Mol Biol 361(5): 850-863.
- Bryk R, Griffin P, Nathan C (2000) Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407(6801): 211-215.
- Wasim M, Bible AN, Xie Z, Alexandre G (2009) Alkyl hydroperoxide reductase has role in oxidative stress resistance and in modulating changes in cell-surface properties in Azospirillum brasilense Sp245. Microbiology 155(Pt 4): 1192-1202.
- Baillon ML, van Vliet AH, Ketley JM, Constantinidou C, Penn CW (1999) An iron-regulated alkyl hydroperoxide reductase (AhpC) confers aerotolerance and oxidative stress resistance to the microaerophilic pathogen Campylobacter jejuni. J Bacteriol 181(16): 4798-4804.
- Kelley VA, Schorey JS (2003) Mycobacterium’s arrest of phagosome maturation in macrophages requires Rab5 activity and accessibility to iron. Mol Biol Cell 14(8): 3366-3377.
- Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, et al. (1995) The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 182(3): 655-666.
- Gomes MS, Appelberg R (1998) Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium. Immunology 95(2): 165-168.
- Zwilling BS, Kuhn DE, Wikoff L, Brown D, Lafuse W(1999) Role of iron in Nramp1-mediated inhibition of mycobacterial growth. Infect Immun 67(3):1386-1392.
- Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, et al.(1998) Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 188(2): 351-364.
- Kuhn DE, Lafuse WP, Zwilling BS (2001) Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line. J Leukoc Biol 69(1): 43-49.
- Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y (2011) Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci 108(48): 19371-19376.
- Gomez MA, Alisaraie L, Shio MT, Berghuis AM, Lebrun C, et al.(2010) Protein tyrosine phosphatases are regulated by mononuclear iron dicitrate. J Biol Chem 285(32): 24620-24628.
- Boelaert JR, Vandecasteele SJ, Appelberg R, Gordeuk VR(2007) The effect of the host's iron status on tuberculosis. J Infect Dis 195(12): 1745-1753.
- Olakanmi O, Britigan BE, Schlesinger L.S(2000) Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect Immun 68(10): 5619-5627.
- Pawaria S, Lama A, Raje M, Dikshit K.L(2008) Responses of Mycobacterium tuberculosis hemoglobin promoters to in vitro and in vivo growth conditions. Appl Environ Microbiol 74(11): 3512-3522.
- Heroux MS, Mohan AD, Olsen KW(2011) Ligand migration in the truncated hemoglobin of Mycobacterium tuberculosis. IUBMB Life 63(3): 214-220.
- Arya S, Sethi D, Singh S, Hade MD, Singh V, et al. (2013) Truncated hemoglobin, HbN, is post-translationally modified in Mycobacterium tuberculosis and modulates host-pathogen interactions during intracellular infection. J Biol Chem 288(41), 29987-29999.
- Yam KC, D'Angelo I, Kalscheuer R, Zhu H, Wang JX, et al. (2009) Studies of a ring-cleaving dioxygenase illuminate the role of cholesterol metabolism in the pathogenesis of Mycobacterium tuberculosis. PLoS Pathog 5(3).
- Capyk, Jenna (2012) Iron-containing monooxygenases in Mycobacterium tuberculosis cholesterol degradation : biochemical and phylogenetic perspectives. The university of British Columbia, Canada.
- Anand PK, Kaul D (2003) Vitamin D3-dependent pathway regulates TACO gene transcription. Biochem Biophys Res Commun 310(3): 876-877.
- Anand PK, Kaul D (2005) Downregulation of TACO gene transcription restricts mycobacterial entry/survival within human macrophages. FEMS Microbiol Lett 250(1): 137-144.
- Ferrari G, Langen H, Naito M, Pieters J (1999) A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 97(4): 435-447.
- Nguyen L, Pieters J (2005) The Trojan horse: survival tactics of pathogenic mycobacteria in macrophages. Trends Cell Biol 15(5): 269-276.
- Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, et al. (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285(5428): 732-736.
- Sugawara I, Yamada H, Kaneko H, Mizuno S, Takeda K, et al. (1999) Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice. Infect Immun 67(5): 2585-2589.
- Yamada H, Mizumo S, Horai R, Iwakura Y, Sugawara I (2000) Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80(5): 759-767.
- Sugawara I, Mizuno S, Yamada H, Matsumoto M, Akira S (2001) Disruption of nuclear factor-interleukin-6, a transcription factor, results in severe mycobacterial infection. Am J Pathol 158(2): 361-366.
- Davis AS, Vergne I, Master SS, Kyei GB, Chua J, et al. (2007) Mechanism of Inducible Nitric Oxide Synthase Exclusion from Mycobacterial Phagosomes. PLoS Pathog 3(12): e186.
- Yamada H, Mizuno S, Ross AC, Sugawara I (2007) Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis. J Nutr 137(12): 2696-2700.
- Liu PT, Modlin RL (2008) Human macrophage host defense against Mycobacterium tuberculosis. Current Opinion in Immunology 20(4): 371-376.
- Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(7): 829-837.
- Cunningham-Bussel A, Zhang T, Nathan CF (2013) Nitrite produced by Mycobacterium tuberculosis in human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression. Proc Natl Acad Sci 110(45): E4256-E4265.
- Crowle AJ, Ross EJ (1989) Inhibition by retinoic acid of multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 57(3): 840-844.
- BIEHL JP, VILTER RW (1954) Effects of isoniazid on pyridoxine metabolism. J Am Med Assoc 156(17): 1549-1552.
- Beggs WH, Jenne JW (1967) Mechanism for the pyridoxal neutralization of isoniazid action of Mycobacterium tuberculosis. J Bacteriol 94(4): 793-797.
- Toosi TD, Shahi F, Afshari A, Roushan N, Kermanshahi M (2008) Neuropathy caused by B12 deficiency in a patient with ileal tuberculosis: a case report. J Med Case Rep 2: 90.
- Frei B, England L, Ames BN (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci 86(16): 6377-6381.
- Podmore .D, Griffiths HR, Herbert KE, Mistry N, Mistry P, et al. (1998) Vitamin C exhibits pro-oxidant properties. Nature 392(6676): 559.
- Anderson R, Hay I, van Wyk H, Oosthuizen R, Theron A (1980) The effect of ascorbate on cellular humoral immunity in asthmatic children. S Afr Med J 58(24): 974-977.
- Panush RS, Delafuente JC, Katz P, Johnson J (1982) Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo lymphocyte responses. Int J Vitam Nutr Res Suppl 23: 35-47.
- Kennes B, Dumont I, Brohee D, Hubert C, Neve P(1983) Effect of vitamin C supplements on cell-mediated immunity in old people. Gerontology 29(5): 305-310.
- Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, et al. (1991) The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing 20(3): 169-174.
- Hemilä H, Kaprio J, Pietinen P, Albanes D, Heinonen OP (1999) Vitamin C and other compounds in vitamin C rich food in relation to risk of tuberculosis in male smokers. Am J Epidemiol 150(6): 632-641.
- DOWNES J (1950) An experiment in the control of tuberculosis among Negroes. Milbank Mem Fund Q 28(2): 127-159.
- Getz HR, Long ER, Henderson HJ (1951) A study of the relation of nutrition to the development of tuberculosis; influence of ascorbic acid and vitamin A. Am Rev Tuberc 64(4): 381-393.
- Madebo T, Lindtjørn B, Aukrust P, Berge RK (2003) Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethiopia. Am J Clin Nutr 78(1): 117-122.
- Vijayamalini M, Manoharan S (2004) Lipid peroxidation, vitamins C, E and reduced glutathione levels in patients with pulmonary tuberculosis. Cell Biochem Funct 22(1): 19-22.
- AHI RS, ARORA D, SINGH R (2010) Oxidative Stress And Ascorbic Acid Levels In Cavitary Pulmonary Tuberculosis. Journal of Clinical and Diagnostic Research 4(6): 3437-3441
- Safarian MD, Karagezian KG, Karapetian ET, Avanesian NA (1990) The efficacy of antioxidant therapy in patients with tuberculosis of the lungs and the correction of lipid peroxidation processes. Probl Tuberk(5): 40-44.
- Vilchèze C, Hartman T, Weinrick B, Jacobs WR Jr (2013) Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun 4 :1881.
- Banerjee D, Bhattacharyya R, Kaul D, Sharma P (2011) Diabetes and tuberculosis: analysis of a paradox. Adv Clin Chem 53: 139-153.
- Banerjee D, Sharma P (2012) Dual effect of glucose on macrophage NADPH oxidase activity: a possible link between diabetes and tuberculosis. Oxid Antioxid Med Sci 1(2): 91-96.
- Bhattacharyya R, Banerjee D (2013) Antioxidants: Friend or foe for tuberculosis patients. Advances in Bioscience and Biotechnology 4 :10-14.
- Aranow C (2011) Vitamin D and the immune system. J Investig Med 59(6):881-886.
- Zasloff, M (2006) Fighting infections with vitamin D. Nat Med 12(4): 388-390.
- Martineau AR, Honecker FU, Wilkinso RJ, Griffiths CJ (2007) Vitamin D in the treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol 103(3-5): 793-798.
- Sasidharan PK, Rajeev E, Vijayakumari V (2002) Tuberculosis and vitamin D deficiency. J Assoc Physicians India 50: 554-558.
- Ustianowski A, Shaffer R, Collin S, Wilkinson RJ, Davidson RN (2005) Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 50(5): 432-437.
- Wejse C, Olesen R, Rabna P, Kaestel P, Gustafson P, et al. (2007) Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls. Am J Clin Nutr 86(5): 1376-1383.
- Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, et al. (2008) Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin Infect Dis 46(3): 443-446.
- Nnoaham KE, Clarke A (2008) Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 37(1): 113-119.
- Williams B, Williams AJ, Anderson ST (2008) Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 27(10): 941-942.
- Rook GA, Steele J, Fraher L, Barker S, Karmali R, et al. (1986) Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57(1): 159-163.
- Rivas-Santiago B, Hernandez-Pando R, Carranza C, Juarez E, Contreras JL, et al. (2008) Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. Infect Immun 2008 Mar 76(3): 935-941.
- Liu PT, Stenger S, Li H, Wenzel L, Tan BH, et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311(5768): 1770-1773.
- Liu PT, Stenger S, Tang DH, Modlin RL (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179(4): 2060-2063.
- Hmama Z, Sendide K, Talal A, Garcia R, Dobos, K, et al. (2004) Quantitative analysis of phagolysosome fusion in intact cells: inhibition by mycobacterial lipoarabinomannan and rescue by an 1alpha,25-dihydroxyvitamin D3-phosphoinositide 3-kinase pathway. J Cell Sci 117(Pt 10): 2131-2140.
- Allavena C, Delpierre C, Cuzin L, Rey D, Viget N, et al. (2012) High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs. J Antimicrob Chemother 67(9): 2222-2230.
- Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR, et al. (2008). Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses 24(11): 1375-1382.
- Selvaraj P (2011) Vitamin D, vitamin D receptor, and cathelicidin in the treatment of tuberculosis. Vitam Horm 86:307-325.
- Plit ML, Theron AJ, Fickl H, van Rensburg CE, Pendel S, et al. (1998). Influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin C, vitamin E, beta-carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2(7): 590-596.
- Kobayashi K, Haruta T, Maeda H, Kubota M, Nishio T, et al. (2002) Cerebral hemorrhage associated with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin. Pediatr Infect Dis J 21(11): 1088-90.