Antioxidants: Friend or foe for tuberculosis patients

doi:10.4236/abb.2013.411A2002

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Advances in Bioscience and Biotechnology, 2013, 4, 10-14 ABB

http://dx.doi.org/10.4236/abb.2013.411A2002 Published Online November 2013 (http://www.scirp.org/journal/abb/)

Antioxidants: Friend or foe for tuberculosis patients

Rajasri Bhattacharyya1, Dibyajyoti Banerjee2*

1Department of Biotechnology, Maharishi Markandeshwar Univer sity, Mullana, Ambala, India

2Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh,

India

Email: *[email protected]

Received 22 August 2013; revised 22 September 2013; accepted 15 October 2013

mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work

is properly cited.

ABSTRACT

Respiratory burst induced bacteria killing by oxi-

dants are important mechanism of host defence.

However, it is impaired in tuberculosis due to inhibi-

tion of respiratory burst by Mycobacterial factors.

Antioxidants are compounds that cause chelation of

reactive oxygen species. So, antioxidants are expected

to play a negative role in the management of active

tuberculosis. But, oxidative st ress is a proved fact that

invariably happens in tuberculosis patients which is

known to cause immunosuppression. Immunosup-

pression in turn is expected to augment tuberculosis.

Hence, antioxidant supplementation is expected to

benefit tuberculosis patients by minimising oxidative

stress induced immunosuppression. Therefore, the

role of antioxidants in tuberculosis appears to be

paradoxical and urgent. Understanding of the role of

antioxidant supplementation in tuberculosis is war-

ranted. It is in this context that we have reviewed the

recent literature and addressed the problem for its

solution.

Keywords: Tubercul osi s; A nt i oxi dants; Reacti ve

Oxygen Species; Clinical Trial; Mycobacterial

tuberculosis

1. INTRODUCTION

Antioxidants are among the most popular health-pro-

tecting products, sold worldwide with out prescription . At

the present moment, there is majority opinion that anti-

oxidants are good for human health but very recently

some researchers are in the opinion that it may not be

good for hu man health un iversall y [1].

In case of infections intracellular generation of ROS/

RNS plays an important role in pathogen clearance.

Phagocytosis is the process by which all pathogens are

engulfed by the macrophages. In the process of phago-

cytosis, a membrane bound vesicle is formed containing

the pathogen. This membrane bound vesicle, is popularly

known as phagosome. Phagosome generally contains

various subunits of NADPH oxidase, the respiratory

burst enzyme (that generates superoxide), iNOS (that

generates peroxynitrite), and many other proteins that

generally undergoes a maturation process by which in-

ternalized particles (such as bacteria and dead cells etc.)

are trafficked into a series of increasingly acidified mem-

brane-bound structures (endosomes, lysosomes), leading

to particle degradation [2 ,3]. It is also now proved that if

the phagosomal ROS is not produced or less produced

the host becomes susceptible to intracellular infections.

The classical example of the above statement is chronic

granulomatous disease which is characterized by dimin-

ished capacity of intracellular ROS production lead ing to

tubercul osi s very often [4].

The role of extracellular antioxidants may be critical

in functioning of intracellular ROS. It is expected that

the available extracellular antioxidant will percolate in-

side the cell and neutralize the nascent ROS. In that case

antioxidants should be harmful in the scenario of active

infections. However, some antioxidants behave as pro-

oxidants in specialized situations. Below an example is

elaborated for explanation of the above mentioned fact.

α-tocopherol (α-TC, Vitamin E) produces α-toco-

pheroxyl radical when it reacts with reactive species su ch

as peroxynitrite [5] or superoxide [6]. α-TC radical is

then recycled to α-TC by other antioxidants such as

ascorbic acid (Vita min C) and glutathione [7-9]. As soon

as ascorbic acid recycles Vitamin E, it is transformed to

the ascorbyl radical, which has a lower reactivity than

α-TC radical [7]. α-TC radical is also recycled to α-TC

by β-carotene [9,10]. So, for proper antioxidant effect

Vitamin E should be administered with another antioxi-

dant and excess amount of vitamin E may be pro-oxidant

*Corresponding a uthor.

OPEN ACCESS

R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14 11

per se. Therefore, it is important to und erstand the role of

vitamin E in various concentrations in presence and ab-

sence of other antioxidants, on the re-ox capacity of in-

tracellular nascent ROS. Similar examples may be cited

with all the commonly used antioxidants and the role of

commonly used antioxidants in intracellular ROS pro-

duction/fu nct i o n is unclear a s on dat e. Such knowledge is

important keeping in mind the prevalence of the infec-

tious diseases and the consumption habit of antioxidants

of public at large. In this article the same will be at-

tempted to be reviewed in the context of tuberculosis.

2. PHAGOSOMAL NICHE FOR

Mycobacterium tuberculosis

Mycobacterium tuberculosis is engulfed by host macro-

phages. It resides inside a stable phagosome which does

not fuse with lysosome for effective bacterial killing.

Such maturation arrest of phagosomes containing My-

cobacterium tuberculosis is thought due to defective re-

cruitment of rab proteins in such phagosomes [11]. My-

cobacterial factor like secreted acid phosphatase is also

thought to be important for inhibition of phagolysosome

biogenesis [12]. As a result the tuberculosis bacterium

resides inside the phagosome without experiencing the

adverse environment produced by lysosomal acid hy-

dr olases. More over Mycobacterium containing phagosom e

recruits cellular iron into the phagosome which is util-

ized for bacterial sustenance [13]. The phagosome is

supposed to posses subunits of NAD PH oxidase, the key

enzyme for respiratory burst which in turn is expected to

generate supero xide. F urther m yelopero xidase i n phagos ome

is known to form hypohalites. Both superoxide and hy-

pohalites are known agents that kill intraphagosomal

parasites. Inducible nitric oxide synthase is also known

to be recruited in phagosomes which generates peroxyni-

trite, the toxic free radical and mediates bacterial killing.

However, Mycobacterial factors are known to inhibit the

function of inducible nitric oxide synthase and NADPH

oxidase and thus less oxidants are produced in Myco-

bacterium tuberculosis containing phagosome, making

the phagosomal pathogen to stay inside a protective

cover [14, 1 5].

3. TUBERCULOSIS AND THE

ANTIOXIDANT PARADOX

Mycobacterium tuberculosis is an intracellular pathogen

and currently infected more than one third of global

population. Like all intracellular pathogens it resides

successfully inside phagosome of macrophages. Myco-

bacterial factors inhibit phagosome maturation so that the

intraphagosomal bacterium is not assaulted by lyso somal

hydrolases [12]. Various bacterial antioxidants are also

proved to counter phagosomal respiratory burst causing

safe stay of the tuberculosis bacterium inside the pha-

gosome [16-18]. In case of atypical Mycobacterium spe-

cies bacterial antioxidants are thought to modulate host

derived oxidative killing mechanisms [19]. In Mycobac-

terium species new antioxidant mechanisms that protect

the bacterium from the phagosomal respiratory burst is

an established phenomenon [20,21]. Even recombinant

BCG over-expressed with superoxide dismutase A con-

fers less protection for development of tuberculosis [22].

Pathogen derived antioxidant mediated escape from pha-

gosomal oxidative burst is not unique for tuberculosis

bacterium and proved to be true in other successful in-

tracellular pathogen as well [23,24]. Host derived anti-

oxidants are also recently proved to be beneficial for

persistence of intracellular pathogen s [25]. Therefore it is

appearing that availability of antioxidants at the pha-

gosome play a negative role for the host in cases of ac-

tive tuberculosis infection.

On the other hand antioxidants like N-acetyl cysteine

is shown to inhibit growth of tuberculosis bacteria inside

tubercular abscess [26]. Such observations are also con-

firmed with other antioxidants like manganese (II) meso-

tetrakis-(N-methylpyridinium-2-yl) porphyrin [27]. Fur-

ther, glutathione is known to modulate the T cell medi-

ated immune response in a manner that reduces the in-

tracellular stability of the tuberculosis bacterium [28].

This fact is observed to be true for many other intracel-

lular infection and so may be considered as a general

phenomenon [29]. Extra cellular superoxide dismutase is

shown to augment phagocytic killing of bacteria [30].

There is evidence in in-vivo studies that control of oxi-

dative stress by supply of antioxidants is beneficial for

prevention and treatment of tuberculosis [31]. In living

human tuberculosis patients oxidative stress is also prov ed

beyond any doubt [32]. The activities of antioxidant en-

zymes are observed to be comparatively less in blood

samples in subjects suffering from active tuberculosis

along with corroborative increase in concentration of pro-

tein carbonyl [33].

Therefore antioxidants if neutralize the phagosomal

oxidants has the chance to augment active form of tu-

berculosis. In other hand if antioxidants are expected to

modulate the immune response to combat intracellular

infection then it may act as a preventive armor for tu-

berculosis. In the context of tuberculosis supplementa-

tion of antioxidants will play beneficial role or not needs

a solution of the paradoxical evidences so far accumu-

lated.

4. SOLUTION OF THE PARADOX

Clinical effect of vitamin E is not observed in recipients

who consume less vitamin C containing diet [34]. It has

been observed that vitamin E supp lementation transien tly

R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14

increases the risk of active tuberculosis in heavy smokers

if co-supplemented with vitamin C [35]. Similar conclu-

sions are arrived in clinical cases of pneumonia [36].

Therefore vitamin C and vitamin E co-supplementation

may be harmful for any infectious disease including tu-

berculosis. It is possible that vitamin C neutralizes to-

copheryl radical that may have microbiocidal role.

Oxidative stress is a proved fact associated with tu-

berculosis [31,32]. Oxidative stress is a phenomenon that

may cause immunosuppression [37]. Oxidative stress

results into defective T cell mediated immunity [38] which

in turn may accelerate tuberculosis infection. Therefore

antioxidant supplementation in tuberculosis patients alo ng

with recommended chemotherapy may help to combat

the oxidative stress mediated defective cell mediated

immunity. In the context of tuberculosis management,

treatment of the cause of the disease is important since

now it is a recognized fact that in the scenario of oxida-

tive stress the management must address the cause of

genesis of the primary disease [39]. However both en-

dogenous and exogenous antioxidants are observed to be

protective against antitubercular drug induced toxicity

[40,41]. Therefore co administration of antioxidants and

anti-tubercular drugs has the potential to serve benefit to

tuberculosis patients for multiple causes. But blind sup-

plementation of antioxidants with anti-tubercular drugs

in tuberculosis patients may cause more harm than bene-

fit. We believe that if oxidative stress develops in a par-

ticular case of tuberculosis appropriate antioxidant sup-

plementation along with antitubercular therapy will ac-

celerate the healing process. Therefore clinical trials in

this direction are warranted to document objective data

to formulate rational antioxidant combination therapy as

an adjunct to antitubercular drug therapy in proved cases

of tuberculosis.

5. ACKNOWLEDGEMENTS

DB acknowledges Department of Biotechnology, Govt. of India for

financial assistance.

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