Medical Hypotheses 84 (2015) 199203

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Combined inhalation and oral supplementation of Vitamin A

and Vitamin D: A possible prevention and therapy for tuberculosis
Kirtimaan Syal a,b, Surajit Chakraborty b, Rajasri Bhattacharyya c, Dibyajyoti Banerjee b,
a

Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
c
Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala 133207, India
b

a r t i c l e

i n f o

Article history:
Received 29 August 2014
Accepted 26 December 2014

a b s t r a c t
Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis
have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics,
making the management more difcult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is
experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is
in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity.
2015 Elsevier Ltd. All rights reserved.

Introduction
Tuberculosis has emerged as a great threat to humankind. Its
MDR (Multi-drug resistant) and XDR (Extensively drug resistant)
strains are becoming even more difcult to treat. Every year, nearly
9.4 million new cases of tuberculosis are reported, making it far
from being contained. Tuberculosis is still the leading cause of premature deaths. Annually, it kills 1.7 million people worldwide [1
9]. Nearly 3 million people suffering from active tuberculosis are
not diagnosed properly and are responsible for the spread of the
disease [10,11]. Its risk factors include poverty, malnutrition, diabetes, smoking, HIV (human immunodeciency virus) infections
and other immunodeciency diseases [12,13]. Tuberculosis is
known for centuries and is successfully surviving despite of worldwide anti-tuberculosis drive. It is present in both developed and
developing worlds. Tuberculosis bacteria are known to cause pulmonary as well as extra pulmonary infections. Pulmonary tuberculosis constitutes to be 8590% of the total cases. Extra pulmonary
tuberculosis is observed in 1015% cases of the tuberculosis infection [14].
Mycobacterium bovis derived Bacille CalmetteGurin (Bacille
de Calmette et Gurin or BCG) vaccine, developed by attenuating
M. bovis by means of in vitro passage, is the only vaccine recommended across the globe. The World Health Organization (WHO)
recommends that all infants should be vaccinated as soon after
birth with a single intradermal dose of BCG in all countries with
Corresponding author. Tel.: +91 172 2755227; fax: +91 172 2744401.
E-mail address: dibyajyoti5200@yahoo.co.in (D. Banerjee).
http://dx.doi.org/10.1016/j.mehy.2014.12.022
0306-9877/ 2015 Elsevier Ltd. All rights reserved.

a high risk of tuberculosis infection. BCG reliability in preventing

the disease in adults is highly debatable [1518]. The potential reasons behind the lowered efcacy of vaccine are predicted as masking hypothesis and blocking hypothesis. The former describes the
sensitization by environmental mycobacteria which results in
low immune response against BCG vaccine and latter attributes
the failure of vaccine to the blocking of efcient replication of
attenuated M. bovis in sensitized population. BCG has been
reported to be majorly effective in children not in adults. Its protection against tuberculosis is doubtful in adults. Till date, there
is no other vaccination regime against tuberculosis that is recommended for the purpose. A major limitation of the BCG vaccination
is its failure to prevent the occurrence of tuberculosis in latent
tuberculosis state. Due to the latter reason, BCG has apparently
failed in preventing the disease. As a result, the condition has deteriorated so much that in current scenario every third person is predicted to be suffering from latent tuberculosis [14,1921].
Due to improper treatment, the global burden of MDR-TB
(multi-drug resistant tuberculosis where the etiological agent
Mycobacterium shows resistance to isoniazid and rifampicin, with
or without resistance to other anti-tuberculosis drugs) has
increased rapidly. The rise of MDR-TB and XDR-TB (extensively
drug resistant tuberculosis where the Mycobacterium is resistant
to at least isoniazid and rifampicin i.e. MDR-TB plus resistance to
any of the uoroquinolones and any one of the second-line injectable drugs viz. amikacin, kanamycin, or capreomycin) have been
majorly observed in China, India, and the Russian Federation
[22,23]. The most disturbing fact is the reporting of 94,000 MDRTB cases in 2012 only, which is nearly one third of the estimated

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K. Syal et al. / Medical Hypotheses 84 (2015) 199203

cases [5]. Tuberculosis is treated with a regime of three lines of

treatment depending on the level of resistance of tuberculosis bacteria. On misuse of rst and second line of drugs, XDR-TB could
emerge. XDR TB is resistant to most of the drugs and available
treatment options become severely limited. Till 2012, 92 countries
reported cases of XDR-TB [5]. BCG vaccination has seemed to be
failing to provide protection as evidenced by the rising number
of new cases. Evolution of bacteria has outpaced the development
and discovery of new drugs. New alternatives to drug therapy are
being looked upon for the treatment of MDR and XDR cases of
tuberculosis [2428]. Malnutrition has been realized as a key risk
factor of tuberculosis and the role of vitamins in curbing infections
have been looked upon for prevention and treatment of tuberculosis [12,13]. Recent evidences indicate the potential of vitamins,
including Vitamin A and Vitamin D in the management of tuberculosis [2933]. Therefore, in the present work we develop a novel
hypothesis involving these two vitamins to control pulmonary
tuberculosis.
Hypothesis
We hypothesize that administration of Vitamin-D in combination with Vitamin-A can be used to treat tuberculosis patients
and the proposed therapy has a potential to be developed as a preventive/vaccine. We propose the administration of Vitamin-A and
Vitamin-D via inhalers and orally to curb the tuberculosis infection
without the plausible side effects or toxicity.
Evaluation of the hypothesis
Infection caused by Mycobacterium tuberculosis is difcult to
treat due to its strategies to evade the innate immunity and thus
it persists inside the host. In fact M. tuberculosis is an intracellular
pathogen which persists inside the TACO (Tryptophan Aspartate
Coat Protein) coated stable phagosome which does not fuse with
lysosome [3437]. TACO dissociation from phagosome is a critical
event for phagolysosome formation which is inhibited in tuberculosis [3740]. Therefore the tuberculosis bacterium is shielded
from immunological microbe killing strategies of the host. Moreover, tuberculosis infected phagosome has less iNOS activity and
less respiratory burst capacity due to mycobacterial factors
[41,42]. Tuberculosis bacterium containing phagosome is known
to accumulate cellular iron, which in-turn accentuates growth of
intracellular pathogen [42]. All these indeed make the tuberculosis
bacterium a very successful pathogen.
Nutrition is known to play pivotal role in immunity against
tuberculosis [4347]. Tuberculosis patients have been shown to
be decient in almost all vitamins. Recently, it has been reported
that tuberculosis patients are decient in both Vitamin A and Vitamin D in comparison to healthy controls [48]. Clinical trials for preventing/curing tuberculosis by Vitamin D administration alone has
failed to yield encouraging results [49].
It should be noted that one of the major pathways through
which Vitamin D is suggested to prevent tuberculosis is by suppression of TACO gene expression which is negatively regulated
by the VDRRXR heterodimer [50,51]. VDR and RXR expression
have been shown to be positively regulated by Vitamin D and Vitamin A respectively [48,50,52,53]. Administration of Vitamin A and
Vitamin D can lead to an increased amount of the supplemented
vitamins in the host. These can in-turn cause RXR and VDR expression which via VDRRXR heterodimerization can limit TACO levels.
Since TACO protein expression is critical for formation of stable
phagosome, reduction of TACO expression for VDRRXR heterodimerization due to Vitamin A and Vitamin D supplementation can
lead to the enhanced phagolysosome formation. This phenomenon

is expected to cause more antigen presentation of the tuberculosis

bacterium generating protective immune response which generally does not occur [5052,5459].
Till date, therapy involving a combination of Vitamin A and
Vitamin D has not been evaluated. It is known that Vitamin A alone
also plays a key role in tuberculosis. Deciency of Vitamin A is
known to increase the susceptibility to infections. The role of Vitamin A in cell mediated immune response is well recognized. It regulates the immune response to infections [41]. However, its
potentiality in treating and preventing tuberculosis in clinical scenario is largely untested. Vitamin A affects the pathogenesis of
tuberculosis by multiple ways. Other than suppression of TACO
expression along with Vitamin D, Vitamin-A and its metabolites
affect the TLR-II signaling and increases the phagocytic activity of
human macrophages [6062]. This in turn is expected to generate
more immunity against the tuberculosis bacterium due to antigen
presentation. Vitamin A has been shown to negatively regulate the
iron receptors in promonocytic cell line in vitro. It was shown to
down-regulate the cellular transferrin receptors [6366]. Therefore, Vitamin A supplementation is expected to reduce cellular
transparency and thus supply of iron in phagosome. Intra-phagosomal iron is critical for tuberculosis infection [42]. Since Vitamin A
is expected to reduce intraphagosomal iron it is also a possible
mechanism of Vitamin A induced anti mycobacterial action. Iron
intake is known to aggravate the infection as mycobacteria need
iron for survival and replication. Therefore intracellular deciency
of iron caused by Vitamin A can certainly limit the spread of infection [6770].
Vitamin A and Vitamin D were given to tuberculosis patients in
the form of cod liver oil since time immemorial [71,72]. Deciency
of Vitamin A and Vitamin D has been linked to susceptibility to
infections and their role in protective immunity is well proven
[71,72]. Recently, the biologically active form of Vitamin A has
been shown to inhibit the growth of virulent M. tuberculosis in
macrophages [73,74]. Therapeutic concentration of 10 5 M has
been suggested to be protective at a post infection stage of tuberculosis and physiological concentration of 10 7 M is predicted to
confer protection against the infection [75]. In presence of Vitamin
A, intracellular generation time for tuberculosis bacteria has been
reported to be increased. Its action has been found to be bacteriostatic in post infection cases [76].
1, 25(OH)2 D3 form of Vitamin D via VDR activates cathelicidinmediated mycobacterial killing. A deciency of 25-hydroxy form of
Vitamin D has been shown to increase the susceptibility to tuberculosis, thus highlighting the vital role played by these vitamins
against tuberculosis [7779].
The role of Vitamin A and Vitamin D in immunity against tuberculosis has been realized, but the mechanism is still unclear. It has
been suggested that Vitamin A acts by overlapping pathways as of
Vitamin D. Further, it has been shown that Vitamin A leads to
decrease in cholesterol content of the cell. Lessening of macrophage membrane cholesterol can be another mechanism of Vitamin A induced control of tuberculosis infection since membrane
cholesterol is a critical factor for the pathogen entry in the macrophage [55]. This Vitamin A induced decrease of cholesterol is
attributed to the function of NPC2, a lysosomal to endoplasmic
reticulum lipid transporter, as a potential mediator of Vitamin A
induced regulation of cellular cholesterol content [80,81]. Under
the inuence of Vitamin A, NPC2 leads to the acidication of lysosomes by an incompletely understood mechanism [8284]. Vitamin A and NPC2 appears to be linked since NPC2 expression is
found to be less in caseous tuberculosis granuloma and its knockout cells are reported to be insensitive to Vitamin A therapy and do
not show Vitamin A mediated antimicrobial action [85,86]. Unlike
Vitamin D, Vitamin A has been reported not to alter the
cathelicidin expression [73,75]. Similarly, Vitamin D increases the

K. Syal et al. / Medical Hypotheses 84 (2015) 199203

phagocytic activity of macrophages and further decreases the stability of phagosome via VDRRXR heterodimer, allowing the phagosomelysosome fusion. Vitamin D also stimulates the production
of the bodys antimicrobial/anti-mycobacterial peptide LL-37, a
member of the cathelicidin peptide family [80]. Altogether, both
vitamins seem to complement (via TACO pathway) as well as supplement each other actions against tuberculosis.
Higher concentration of Vitamin A and Vitamin D at the site of
infection is desirable. Vitamin A at 10 4 M is reported to diminish
bacillary growth in vitro, but at 10 5 M and lower concentrations, it
had no effect [75]. Also, Vitamin D has been shown to inhibit at
10 5 M concentration in vitro and lower concentration has relatively less or no effect [58]. Vitamin A and Vitamin D at such concentrations can cause toxicity [7681]. So, we recommend
inhalation as the mode of administration of these vitamins in addition to recommended doses of oral supplementation. This mode of
administration is expected to deliver more pharmaceuticals at the
lung tissue with chance of minimal toxicity.
Administration of Vitamin A and Vitamin D via inhalers can
deliver the essential vitamins directly to the site of infection and
can achieve high concentration at the infection site instantly. Combined administration of Vitamin A and Vitamin D is expected to
limit the pathogenesis of tuberculosis due to afore- mentioned reasons. We advocate the immediate testing of combined administration of Vitamin A and Vitamin D via inhalers in animal model
systems and subsequent clinical trials in humans for toxicity and
efciency. The major grounds for the presented hypothesis are provided in a ow chart for understanding of the readers (Fig. 1).

201

To test the presented hypothesis, large scale studies should be

performed to monitor the incidence of tuberculosis in population
supplemented with the Vitamins (by inhalation and oral) in comparison to appropriate controls. Clinical trials should be immediately conducted after getting positive results from animal studies
in endemic areas, keeping in mind both the preventive and curative mode of the developed strategy. MDR/XDR cases should be
included in the study where patients with ongoing therapy should
be compared with patients treated with ongoing therapy in addition with vitamin supplements (via oral and inhalation route)
and prognosis in patients should be evaluated. Since XDR/MDR
strains are largely resistant to most of the available antibiotics,
therefore such supplementation therapy has a potential to offer
treatment for all types of resistant M. tuberculosis infection. Further
administration of vitamins should be tested via inhalers for antimicrobial activity in comparison to the oral supplementation alone
and combined supplementation.

Concluding remarks
Tuberculosis is a disease with history. With advent of antibiotics, many infectious diseases are having better management outcomes. Due to misuse of drugs, tuberculosis has re-emerged in
MDR and XDR forms which are very difcult to treat. Today, therapies for treating MDR and XDR tuberculosis have become severely
limited. BCG vaccine has failed in preventing the disease in adults.
Development of new vaccines is an ongoing challenge. In current

Fig. 1. The scheme of molecular events for the possible immune-protective or vaccine like activity of combination of Vitamin-A and Vitamin-D therapy. Vitamin-A has been
shown to down-regulate the expression of transferrin receptor at transcriptional level which in turn may lower the required iron supply for intracellular M. tuberculosis.
Moreover, it has been shown to alter the TLR-II signaling pathway and affect mycobacterial survival. Combination of Vitamin-A and Vitamin-D decreases the TACO level and
thus enhances phagosomelysosome fusion which in turn may increase the intracellular killing M. tuberculosis. Vitamin-D has shown to enhance the antimicrobial role of
peptide Cathelicidin family. It has found to decrease the host macrophage cholesterol level via NPC2 down-regulation pathway. Decrease in host cell cholesterol is believed to
restrict mycobaterial entry. All these may lead to an increased phagocytic killing of M. tuberculosis and in turn may enhance Class-II antigen presentation and confer
protection against tuberculosis infection. For details kindly refer the text. (See above-mentioned references for further information.)

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K. Syal et al. / Medical Hypotheses 84 (2015) 199203

scenario, Vitamin A and Vitamin D supplements may provide an

alternative to drug therapy. Also, treatment via vitamin supplementation through a host based therapeutic approach should work
irrespective of the level of resistance (MDR, XDR or TDR) in bacteria. They may give protection to the susceptible population and
have a potential for working as a preventive strategy. Most of the
antibiotics are known to target M. tuberculosis and do not play
any role in building up immunity in host against the infection
and spread. Combined Vitamin A and Vitamin D supplementation
therapy has the potential of killing the bacteria directly as well
as to boost the host immunity against the infection, which may fasten up the prognosis and thus offer both host based and pathogen
targeted treatment of the disease [72,89]. Excessive oral supplementation of Vitamin A and D can exceed the therapeutic plasma
concentration and cause toxicity [9094]. Therefore, combination
of oral and inhalational delivery route of the vitamins felt justied.
With the rapid emergence of resistance in TB bacteria, vitamins
look promising as an alternative to antibiotics [50,95,96]. Combination of Vitamin A and Vitamin D can boost immunity against
tuberculosis and can help in better prognosis. Administration of
different combinations of Vitamin A and Vitamin D via inhalers
directly to the site of infection should be analyzed [62,73,97
103]. We suggest regular campaigns for administration of these
vitamins in endemic areas if our hypothesis is proved to be a fact
in systematic clinical trials. Such types of events may help in
improving the health of the population and can confer the immunity against the disease.
Conict of interest statement
Authors do not have any conict of interest.
Acknowledgements
DB thanks Department of Biotechnology, Govt. of India for
nancial assistance.
References
[1] WHO. Global tuberculosis control: 2010 Geneva. Available at <http://www.
who.int/tb/publications/global_report/2010/en/>
2010
[accessed
on
19.08.2014].
[2] Merte JL, Kroll CM, Collins AS, Melnick AL. An epidemiologic investigation of
occupational transmission of Mycobacterium tuberculosis infection to dental
health care personnel: infection prevention and control implications. J Am
Dent Assoc 2014;145(5):46471.
[3] Conversano M. Update on the epidemiology of tuberculosis in Italy. J
Rheumatol Suppl 2014;9:410.
[4] Chitnis AS, Schecter GF, Cilnis M, Robsky K, Flood JM, Barry PM. Epidemiology
of tuberculosis cases with end-stage renal disease, California, 2010. Am J
Nephrol 2014;39(4):31421.
[5] Matteelli A, Roggi A, Carvalho AC. Extensively drug-resistant tuberculosis:
epidemiology and management. Clin Epidemiol 2014;6:1118.
[6] Dheda K, Gumbo T, Gandhi NR, Murray M, Theron G, Udwadia Z, et al. Global
control of tuberculosis: from extensively drug-resistant to untreatable
tuberculosis. Lancet Respir Med 2014;2(4):32138.
[7] Francis JR, Blyth CC, Colby S, Fagan JM, Waring J. Multidrug-resistant
tuberculosis in Western Australia, 19982012. Med J Aust 2014;200(6):
32832.
[8] Rieder HL. The dynamics of tuberculosis epidemiology. Indian J Tuberc
2014;61(1):1929.
[9] Migliori GB, Sotgiu G. Measuring the effect of tuberculosis control: a step
forward. Lancet 2014;383(9934):20268. http://dx.doi.org/10.1016/S01406736(14)60032-5.
[10] Herbert N, George A, Baroness Masham of I, Sharma V, Oliver M, Oxley A, et al.
World TB Day 2014: nding the missing 3 million. Lancet
2014;383(9922):10168. Mar 22.
[11] A new brand for tuberculosis. Lancet 2014; 383(9922):1014.
[12] Narasimhan P, Wood J, MacIntyre CR, Mathai D. Risk Factors for Tuberculosis.
Pulmonary Medicine 2013. <http://dx.doi.org/10.1155/2013/828939>.
[13] Tulu B, Dida N, Kassa Y, Taye B. Smear positive pulmonary tuberculosis and its
risk factors among tuberculosis suspect in South East Ethiopia; a hospital
based cross-sectional study. BMC Res Notes 2014;7:285. <http://www.
biomedcentral.com/1756-0500/7/285>.

[14] Andersen P, Doherty TM. The success and failure of BCG implications for a
novel tuberculosis vaccine. Nat Rev Microbiol 2005;3(8):65662.
[15] Parkash O. Vaccine against tuberculosis: a view. J Med Microbiol 2014;63(Pt
6):7779. http://dx.doi.org/10.1099/jmm.0.070425-0.
[16] Zenteno-Cuevas R. Update on the development of TB Vaccines. Curr Pharm
Biotechnol 2014;14(11):9406.
[17] Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PE, et al. Protection
by BCG vaccine against tuberculosis: a systematic review of randomized
controlled trials. Clin Infect Dis 2014;58(4):47080.
[18] McShane H. Understanding BCG is the key to improving it. Clin Infect Dis
2014;58(4):4812.
[19] Palavecino CE, Cespedes PF, Gomez RS, Kalergis AM, Bueno SM. Immunization
with a recombinant bacillus Calmette-Guerin strain confers protective Th1
immunity against the human metapneumovirus. J Immunol 2014;192(1):
21423.
[20] Delogu G, Manganelli R, Brennan MJ. Critical research concepts in tuberculosis
vaccine development. Clin Microbiol Infect 2014;20(Suppl 5):5965.
[21] Harris SA, Meyer J, Satti I, Marsay L, Poulton ID, Tanner R, et al. Evaluation of a
human BCG challenge model to assess antimycobacterial immunity induced
by BCG and a candidate tuberculosis vaccine, MVA85A, alone and in
combination. J Infect Dis 2014;209(8):125968.
[22] Health and Research Topics. National Institute of Allergy and Infectious
Diseases.
Available
at <http://www.niaid.nih.gov/topics/tuberculosis/
understanding/whatistb/pages/tbdenitions.aspx>. [accessed on 19.08.2014].
[23] Multidrug-resistant tuberculosis (MDR-TB) (October 2013 Update). World
Health Organization. Available at <http://www.who.int/tb/challenges/mdr/
mdr_tb_factsheet.pdf?ua=1>. [accessed on 19.08.2014].
[24] van der Werf MJ, Sprenger M. Drug-resistancea challenge for tuberculosis
control in the European Union and European Economic Area. Euro Surveill
2014;19(11).
[25] van der Werf MJ, Kodmon C, Hollo V, Sandgren A, Zucs P. Drug resistance
among tuberculosis cases in the European Union and European Economic
Area, 2007 to 2012. Euro Surveill. 2014;19(10).
[26] McGrath M, Gey van Pittius NC, van Helden PD, Warren RM, Warner DF.
Mutation rate and the emergence of drug resistance in Mycobacterium
tuberculosis. J Antimicrob Chemother 2014;69(2):292302.
[27] Nebenzahl-Guimaraes H, Jacobson KR, Farhat MR, Murray MB. Systematic
review of allelic exchange experiments aimed at identifying mutations that
confer drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother
2014;69(2):33142.
[28] Rajendran V, Sethumadhavan R. Drug resistance mechanism of PncA in
Mycobacterium tuberculosis. J Biomol Struct Dyn 2014;32(2):20921.
[29] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D1,2. Am J
Clin Nutr 2007;85:618.
[30] Holick MF, Chen TC. Vitamin D deciency: a worldwide problem with health
consequences14. Am J Clin Nutr 2008;87(Supp.l):1080S6S.
[31] Vitamin D and Health. Harvard School of Public Health. Available at <http://
www.hsph.harvard.edu/nutritionsource/vitamin-d/>. [accessed on 19.08.2014].
[32] Dini C, Bianchi A. The potential role of vitamin D for prevention and
treatment of tuberculosis and infectious diseases. Ann Ist Super Sanit
2012;48(3):31927. http://dx.doi.org/10.4415/ANN_12_03_13.
[33] Zhang R, Naughton DP. Vitamin D in health and disease: current perspectives.
Nutr J 2010;9:65.
[34] Koul A, Herget T, Klebl B, Ullrich A. Interplay between mycobacteria and host
signalling pathways. Nat Rev Microbiol 2004;2:189202. http://dx.doi.org/
10.1038/nrmicro840.
[35] Russell DG. Mycobacterium tuberculosis: here today, and here tomorrow. Nat
Rev Mol Cell Biol 2001;2:56986. http://dx.doi.org/10.1038/35085034.
[36] Tailleux L, Neyrolles O, Honor-Bouakline S, et al. Constrained intracellular
survival of Mycobacterium tuberculosis in human dendritic cells. J Immunol
2003;170:193948. http://dx.doi.org/10.4049/jimmunol.170.4.1939.
[37] Ferrari G, Langen H, Naito M, Pieters J. Acoat protein on phagosomes involved
in the intracellular survival of mycobacteria. Cell 1999;97:43547.
[38] Nguyen L, Pieters J. The Trojan horse: survival tactics of pathogenic
mycobacteria in macrophages. Trends Cell Biol 2005;15:26976.
[39] Vergne I et al. Mycobacterium tuberculosis phagosome maturation arrest:
mycobacterial phosphatidylinositol analog phosphatidylinositol mannoside
stimulates early endosomal fusion. Mol Bio Cell 2004;15:75160.
[40] Banerjee D, Bhattacharyya R. Statin therapy may prevent development of
tuberculosis in diabetic state. Med Hypothesis 2014;83:8891.
[41] Tomioka H, Tatano Y, Maw WW, Sano C, Kanehiro Y, Shimizu T.
Characteristics of Suppressor Macrophages Induced by Mycobacterial and
Protozoal Infections in relation to Alternatively Activated M2Macrophages.
Clin Dev Immunol 2012. http://dx.doi.org/10.1155/2012/635451.
[42] Johnson EE, Sandgren A, Cherayil BJ, Murray M, Wessling-Resnick M. Role of
ferroportin
in
macrophage-mediated
immunity.
Infect
Immun
2010;78(12):5099106. http://dx.doi.org/10.1128/IAI.00498-10.
[43] Dye C, Bourdin Trunz B, Lonnroth K, Roglic G, Williams BG. Nutrition, diabetes
and tuberculosis in the epidemiological transition. PLoS One 2011;6(6):
e21161.
[44] Gupta KB, Gupta R, Atreja A, Verma M, Vishvkarma S. Tuberculosis and
nutrition. Lung India. 2009;26(1):916.
[45] Nutrition and susceptibility to tuberculosis. Nutr Rev. 1952; 10(5):141-2.
[46] Getz HR, Long ER, Henderson HJ. A study of the relation of nutrition to the
development of tuberculosis; inuence of ascorbic acid and vitamin A. Am
Rev Tuberc 1951;64(4):38193.

K. Syal et al. / Medical Hypotheses 84 (2015) 199203

[47] The Effect of Nutrition on the Course of Tuberculosis. Science. 1945 May
25;101(2630):531.
[48] Srinivasan A, Syal K, Banerjee D, Hota D, Gupta D, Kaul D, et al. Low plasma
levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications
in host-based chemotherapy. Nutrition 2013;29(10):124551.
[49] Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, et al.
High-dose vitamin D3 during intensive-phase antimicrobial treatment of
pulmonary tuberculosis: a double-blind randomised controlled trial. The
Lancet 2011;377(9761):24250.
[50] Anand PK, Kaul D, Sharma M. Synergistic action of vitamin D and retinoic acid
restricts invasion of macrophages by pathogenic mycobacteria. J Microbiol
Immunol Infect 2008;41(1):1725.
[51] Anand PK, Kaul D. Vitamin D3-dependent pathway regulates TACO gene
transcription. Biochem Biophys Res Commun 2003;310(3):8767.
[52] Anand PK, Kaul D. Downregulation of TACO gene transcription restricts
mycobacterial entry/survival within human macrophages. FEMS Microbiol
Lett 2005;250(1):13744.
[53] Dave VP, Kaul D, Sharma M. Crosstalk between RXR, LXR and VDR within
blood mononuclear cellular model. Indian J Exp Biol 2012;50(1):3540.
[54] Anand PK, Kaul D, Sharma M. Green tea polyphenol inhibits Mycobacterium
tuberculosis survival within human macrophages. Int J Biochem Cell Biol
2006;38(4):6009.
[55] Kaul D, Anand PK, Verma I. Cholesterol-sensor initiates M. tuberculosis entry
into human macrophages. Mol Cell Biochem 2004;258(12):21922.
[56] Pieters J. Entry and survival of pathogenic mycobacteria in macrophages.
Microbes Infect. 2001;3(3):24955.
[57] Mitsuyama M, Suzuki K. Mechanisms of pathogenicity and host defense in
infections by intracellular parasitic microbes. Kekkaku 2000;75(9):55760.
[58] Ferrari G, Langen H, Naito M, Pieters J. A coat protein on phagosomes involved
in the intracellular survival of mycobacteria. Cell 1999;97(4):43547.
[59] Syal K, Srinivasan A, Banerjee D. VDR, RXR, coronin-1 and interferon c levels
in PBMCs of type-2 diabetes patients: molecular link between diabetes and
tuberculosis. Ind J Clin Biochem 2014;11:16.
[60] Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the
human immune response. Ann N Y Acad Sci 2007;1117:94105. http://
dx.doi.org/10.1196/annals.1402.036.
[61] Coussens AK, Martineau AR, Wilkinson RJ. Anti-inammatory and
antimicrobial actions of vitamin D in combating TB/HIV. Scientica 2014.
<http://dx.doi.org/10.1155/2014/903680>.
[62] Chakraborty S, Syal K, Bhattacharyya R, Banerjee D. Vitamin deciency and
tuberculosis: need for urgent clinical trial for management of tuberculosis. J
Nutr Health Food Sci 2014;2(2):16.
[63] Iturralde M, Vass JK, Oria R, Brock JH. Effect of iron and retinoic acid on the
control of transferrin receptor and ferritin in the human promonocytic cell
line U937. Biochim Biophys Acta 1992;1133(3):2416.
[64] Jorgensen MJ, Fisker AB, Erikstrup C, Claesson MH, Benn CS. SNP may modify
the effect of vitamin A supplementation at birth on cytokine production in a
whole blood culture assay. Br J Nutr 2012;107(5):61520.
[65] Krutzik SR, Hewison M, Liu PT, Robles JA, Stenger S, Adams JS, et al. IL-15 links
TLR2/1-induced macrophage differentiation to the vitamin D-dependent
antimicrobial pathway. J Immunol 2008;181(10):711520.
[66] Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR
partnership. Trends Mol Med 2007;13(3):11724.
[67] Pandey SD, Choudhury M, Yousuf S, Wheeler PR, Gordon SV, Ranjan A, et al.
Iron-regulated protein HupB of Mycobacterium tuberculosis positively
regulates siderophore biosynthesis and is essential for growth in
macrophages. J Bacteriol 2014;196(10):185365.
[68] Gong L, Yuan F, Teng J, Li X, Zheng S, Lin L, et al. Weight loss, inammatory
markers, and improvements of iron status in overweight and obese children. J
Pediatr 2014;164(4):795800. e2.
[69] Wareham AS, Tree JA, Marsh PD, Butcher PD, Dennis M, Sharpe SA. Evidence
for a role for interleukin-17, Th17 cells and iron homeostasis in protective
immunity against tuberculosis in cynomolgus macaques. PLoS One
2014;9(2):e88149.
[70] Chim N, Johnson PM, Goulding CW. Insights into redox sensing
metalloproteins in Mycobacterium tuberculosis. J Inorg Biochem 2014;133:
11826.
[71] Zasloff M. Fighting infections with vitamin D. Nat Med 2006;12(4):38890.
[72] Martineau AR, Honecker FU, Wilkinso RJ, Grifths CJ. Vitamin D in the
treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol
2007;103(35):7938.
[73] Wheelwright M, Kim EW, Inkeles MS, De Leon A, Pellegrini M, Krutzik SR,
et al. All-trans retinoic acid-triggered antimicrobial activity against
Mycobacterium tuberculosis is dependent on NPC2. J Immunol 2014;192(5):
228090.
[74] Rook GA, Steele J, Fraher L, Barker S, Karmali R, ORiordan J, et al. Vitamin D3,
gamma interferon, and control of proliferation of Mycobacterium tuberculosis
by human monocytes. Immunology 1986;57(1):15963.
[75] Crowle AJ, Ross EJ. Inhibition by retinoic acid of multiplication of virulent
tubercle bacilli in cultured human macrophages. Infect Immun 1989;57(3):
8404.

203

[76] Ali W, Ahmad I, Srivastava VK, Prasad R, Kushwaha RA, Saleem M. Serum zinc
levels and its association with vitamin A levels among tuberculosis patients. J
Nat Sci Biol Med 2014;5(1):1304.
[77] Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor
triggering of a vitamin D-mediated human antimicrobial response. Science
2006;311(5768):17703.
[78] Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, Ebeling PR, et al.
Vitamin D deciency is associated with tuberculosis and latent tuberculosis
infection in immigrants from sub-Saharan Africa. Clin Infect Dis
2008;46(3):4436.
[79] Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated
human antimicrobial activity against Mycobacterium tuberculosis is
dependent on the induction of cathelicidin. J Immunol 2007;179(4):20603.
[80] Du X, Yang H. Endosomal cholesterol trafcking: protein factors at a glance.
Acta Biochim Biophys Sin 2012;45:17. http://dx.doi.org/10.1093/abbs/
gms095.
[81] Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL.
NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid
bilayers, a step in cholesterol egress from lysosomes. PNAS 2008;105(40):
1528792.
[82] Ullery JC. The effects of triglyceride on lysosomal function in macrophage
foam cells. Available at <http://etd.library.vanderbilt.edu/available/etd07242009202301/unrestricted/Ullery_Dissertation_Final_Copy.pdf>
[83] Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for
lysosomal membrane proteins. Trends Cell Biol 2003;13(3):13744.
[84] Fielding JC, Fielding PE. Intracellular cholesterol transport. J Lipid Res
1997;38. 1503-152.
[85] Wheelwright M, Kim EW, Inkeles MS, et al. All-trans retinoic acid-triggered
antimicrobial activity against Mycobacterium tuberculosis is dependent on
NPC2. J Immunol 2014;192(5):228090.
[86] Liu P, Kim E, Wheelwright M, Krutzik S. All-trans retinoic acid-induced
antimicrobial activity against M. tuberculosis is dependent on NPC2mediated reulation of cellular cholesterol. J Immunol 2012;188.
[87] Harding CV, Boom WH. Regulation of antigen presentation by Mycobacterium
tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol
2010;8(4):296307. http://dx.doi.org/10.1038/nrmicro2321.
[88] Shin DM, Jo EK. Antimicrobial Peptides in Innate Immunity against
Mycobacteria. Immune Netw 2011;11(5):24552.
[89] Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the
multiplication of virulent tubercle bacilli in cultured human macrophages.
Infect Immun 1987;55(12):294550.
[90] Broulik PD, Raska I, Broulikova K. Prolonged overdose of all-trans retinoic acid
enhances bone sensitivity in castrated mice. Nutrition 2013;29(9):11669.
[91] Kolodzinska A, Heleniak A, Ratajska A. Retinoic acid-induced ventricular noncompacted cardiomyopathy in mice. Kardiol Pol 2013;71(5):44752.
[92] Pandita KK, Razdan S, Kudyar RP, Beigh A, Kuchay S, Banday T. Excess gooD
can be Dangerous. A case series of iatrogenic symptomatic hypercalcemia
due to hypervitaminosis D. Clin Cases Miner Bone Metab 2012;9(2):11820.
[93] Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation
and risk of toxicity in pediatrics: a review of current literature. J Clin
Endocrinol Metab 2014;99(4):113241.
[94] Guerra JM, Daniel AG, Aloia TP, de Siqueira A, Fukushima AR, Simoes DM,
et al. Hypervitaminosis A-induced hepatic brosis in a cat. J Feline Med Surg
2014;16(3):2438.
[95] Rutkowski M, Grzegorczyk K. Adverse effects of antioxidative vitamins. Int J
Occup Med Environ Health 2012;25(2):10521.
[96] Vilchze C, Hartman T, Weinrick B, Jacobs WR. Mycobacterium tuberculosis is
extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction.
Nat Commun [Article] 2013;4:1881.
[97] Borella E, Nesher G, Israeli E, Shoenfeld Y. Vitamin D: a new anti-infective
agent? Ann N Y Acad Sci 2014;1317:7683. http://dx.doi.org/10.1111/
nyas.12321.
[98] Konstantinos A. Vitamin D and tuberculosis. Med J Aust. 2014;200(5):264.
[99] Wingeld T, Schumacher SG, Sandhu G, Tovar MA, Zevallos K, Baldwin MR,
et al. The seasonality of tuberculosis, sunlight, vitamin D, and household
crowding. J Infect Dis 2014. http://dx.doi.org/10.1093/infdis/jiu121.
[100] Zheng Y, Li XG, Wang QZ, Ma AG, Bygbjerg IC, Sun YY, et al. Enhancement of
vitamin A combined vitamin D supplementation on immune response to
Bacille Calmette-Guerin vaccine revaccinated in Chinese infants. Asian Pac J
Trop Med 2014;7(2):1305.
[101] Garcia de Tena J, El Hachem Debek A, Hernandez Gutierrez C, Izquierdo
Alonso JL. The Role of vitamin D in chronic obstructive pulmonary disease,
asthma and other respiratory diseases. Arch Bronconeumol 2014;50(5):
17984.
[102] Huaman MA, Sterling TR, Shepherd BE, Fiske CT. 25-Hydroxyvitamin D levels
after recovery from tuberculosis: insights into pathogenesis. Tuberculosis
(Edinb) 2014;94(1):514.
[103] Pakpoor J. The role of vitamin D in the association between tuberculosis and
end-stage renal disease. Epidemiol Infect 2014;142(4):8867.