Dietary Antioxidants: Immunity and Host Defense

1752 Current Topics in Medicinal Chemistry, 2011, 11, 1752-1766
1568-0266/11 $58.00+.00 2011 Bentham Science Publishers Ltd.

Dietary Antioxidants: Immunity and Host Defense
Mara A. Puertollano, Elena Puertollano, Gerardo lvarez de Cienfuegos and Manuel A. de Pablo*
Division of Microbiology, Department of Health Sciences, Faculty of Experimental Sciences, University of Jan,
E-23071, Jan Spain
Abstract: Natural antioxidants may be defined as molecules that prevent cell damage against free radicals and are critical
for maintaining optimum health in both animals and humans. In all living systems, cells require adequate levels of anti-
oxidant defenses in order to avoid the harmful effect of an excessive production of reactive oxygen species (ROS) and to
prevent damage to the immune cells. During the inflammatory processes, the activation of phagocytes and/or the action of
bacterial products with specific receptors are capable of promoting the assembly of the multicomponent flavoprotein
NADPH oxidase, which catalyzes the production of high amounts of the superoxide anion radical (O
2
-
). Under these par-
ticular circumstances, neutrophils and macrophages are recognized to produce superoxide free radicals and H
2
O
2
, which
are essential for defence against phagocytized or invading microbes. In this state, antioxidants are absolutely necessary to
regulate the reactions that release free radicals. Antioxidant nutrients commonly included in the diet such as vitamin E, vi-
tamin C, -carotene, selenium, copper, iron and zinc improve different immune function exhibiting an important protec-
tive role in infections caused by bacteria, viruses or parasites. As a result, dietary antioxidants have been related to modu-
late the host susceptibility or resistance to infectious pathogens. Overall, numerous studies have suggested that the devel-
opment of tolerance, and control of inflammation are strongly correlated with specific immune mechanisms that may be
altered by an inadequate supply of either macronutrients or micronutrients. Therefore, the present paper will review the ef-
fects of dietary antioxidants on immune cell function and the impact on protection against infectious microorganisms.
Keywords: Dietary antioxidants, immune system, infection, vitamins, trace elements.
1. INTRODUCTION
The immune system of vertebrate organisms may be de-
scribed as a highly effective and complex network of cells
and factors, perfectly orchestrated and coordinated, that pro-
tects the host from infectious and pathogenic microorgan-
isms. It recognises and destroys foreign agents through two
primary defense mechanisms: innate immunity and acquired
immunity. The innate immune system (non specific immune
response) is present at birth and includes physiologic barriers
(skin, mucous membranes, body temperature, low pH, and
special chemical mediators such as complement and inter-
feron), specialized cells (natural killer [NK] cells, and
phagocytes including neutrophils, monocytes, and macro-
phages which can engulf, kill, and digest whole microorgan-
isms), and inflammatory mediators. On the other hand, the
acquired immune system (specific immune response) is ac-
quired later in life (immunization or exposition to pathogens)
and includes special cells called B- and T-lymphocytes that
are capable of secreting a large variety of specialized chemi-
cals (antibodies and cytokines) to regulate the immune re-
sponse. T lymphocytes can be divided into two fundamental
groups: on the one hand, Th1 lymphocytes, which are regu-
lated by interleukin-12 (IL-12) and interferon- (IFN-),
produce pro-inflammatory cytokines (such as IL-2 or IFN-)
and activate macrophages, NK cells and cytotoxic T lym-
phocytes; on the other hand, Th2 lymphocytes which are
regulated by IL-4, and are specialized in the production of
*Address correspondence to this author at the Universidad de Jan, Facultad
de Ciencias Experimentales, Departamento de Ciencias de la Salud, rea de
Microbiologa, E-23071-Jan, Spain; Tel: +34 953 212 003; Fax: +34 953
212 943; E-mail: : mapablo@ujaen.es
cytokines with an anti-inflammatory activity such as IL-4,
IL-5, IL-10 and IL-13. Hence, infection with intracellular
pathogens will induce the differentiation along the Th1
pathway, whereas infection with extracellular pathogens will
promote the differentiation along the Th2 pathway. Once the
body has identified the antigen, the immune system response
to a second exposition is faster and more effective the next
time that antigen is recognized. Thus, the infectious agent is
eliminated and immunological memory remains Fig. (1).
However, many of the protective functions of immune
cells depend on cell membrane fluidity. It is clear that lipid
peroxidation decreases membrane fluidity, which adversely
affects immune responses. Therefore, the relevance of anti-
oxidants is particularly critical for the functionality of im-
mune system.
Nutritional status is an important factor contributing to
immunocompetence and the profound interactions among
nutrition, infection, and immune system have widely been
recognised [1, 2]. Nowadays, it is clearly established that
nutritional deficiency is related to an inadequate function of
immune response, especially cell-mediated immunity,
phagocyte activity, cytokine production, or antibody synthe-
sis. In addition to protein-energy malnutrition, deficiencies
of trace elements, vitamins and essential fatty acids are re-
sponsible for an impairment of immunity [3]. In the last
years numerous investigations have focused on the role of
nutrition and particularly on the contribution of dietary anti-
oxidants to an optimum and adequate functioning of the im-
mune system. Since antioxidants constitute our first line of
defense against free radical damage and are crucial for main-
taining optimum health, the need for antioxidants becomes
Dietary Antioxidants: Immunity and Host Defense Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 14 1753
Fig. (1). Schematic representation of both innate and acquired immune response. Abbreviations: IFN-, interferon-; IL, interleukin; NK,
natural killer.
even more critical with increased exposure to free radicals,
which promote harmful activities associated with injury to
cells and the body, causing damage to cell membranes, en-
zymes, and DNA.
The immune system is especially sensitive to oxidative
stress. Cells that constitute the immune system depend on
cell-cell communication, via membrane-bound receptors, to
carry out an adequate transmission of signals. Cell mem-
branes are rich in phospholipids which, if peroxidized, can
lead to a loss of membrane integrity, to an alteration of
membrane fluidity [4] , and as a result both cell functions
and intracellular signalling are intensely impaired. It has
been demonstrated that exposure to potential pro-oxidants
can involve a reduction in cell-membrane receptor expres-
sion in those cells that are not suitably protected by antioxi-
dants [5]. For these reasons, it is obvious that adequate
amounts of neutralising antioxidants not only are required to
protect cells against oxidative stress, but also to prevent
damage of the immune cells reducing morbidity and mortal-
ity. By contrast, insufficient intake and status of dietary anti-
oxidants may lead to a profound suppression of immune
functions, which increases the risk of sepsis and predisposes
to infections.
2. FREE RADICALS AND OXIDATIVE STRESS
Oxygen radical are identified as mediators of various
degenerative diseases and inflammatory disorders such as
1754 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 14 Puertollano et al.
diabetes, cancer, rheumatoid arthritis, brain dysfunctions and
immune alterations. Accordingly, cells that constitute our
immune system are particularly sensitive to oxidative stress,
because cell membranes are mainly composed by fatty acids.
In addition, many immune cells produce ROS as part of the
bodys defence against infection. Levels of ROS are bal-
anced by the neutralizing activity of antioxidant molecules
and enzymes, thereby preventing excessive damage to the
host. Hence, it is very easy to assume that cells of immune
system require more concentrations of antioxidants than
other type of cells due particularly to these characteristics.
Obviously, the oxidant/antioxidant balance is a crucial de-
terminant that contributes to improve immune cell function,
not only for preserving integrity and functionality of lipids
that constitute plasma membrane, but also for protecting
cellular proteins and nucleic acids, and consequently for
regulating signal transduction and gene expression in im-
mune cells. Redox state of the cells may activate nuclear
factor-B (NF-B), an inducible transcription factor that can
rapidly regulate the expression of genes involved in inflam-
matory responses [6]. Thus, regulation of NF-B by oxida-
tive stress status of the host can have a substantial effect on
the host response to infection. A schematic representation of
upregulation of inflammatory gene expression by NF-B
pathway is illustrated in Fig. (2).
The term free radicals is referred to an important family
of compounds highly reactive due to the unpaired electrons
in the outer orbital. To this wide group belongs ROS, such as
superoxide anion (O
2
-
), hydroxyl radical (
OH) and hydro-

gen peroxide (H
2
O
2
), as well as reactive nitrogen species
(RNS) which include nitric oxide (NO) and peroxynitrite
(ONOO
-
). Free radicals are generated as a result of cell
metabolic activity and as an immune system strategy to
eliminate invading agents. For example, O
2
-
plays an essen-
tial role in the intracellular killing of microorganisms by
activated phagocytes. All the major classes of biomolecules
are vulnerable to free radical damage. Consequently, free
radicals cause strand breaks in DNA, which potentially can
lead to subsequent misrepair and tumour cell generation.
However, long-chain lipids (particularly polyunsaturated
fatty acids, which contain double bonds) are more suscepti-
ble to free radical attack, leading to lipid oxidative destruc-
tion of fatty acids called lipid peroxidation, a key conse-
quence of oxidative stress [7]. Thus, ROS react with the
double bond of polyunsaturated lipids, producing unstable
lipid peroxides that may cause cell death [8].
During evolution organisms have evolved antioxidant
defence systems to either evade (neutralize) the generation of
free radicals or to intercept any that are detected. These pro-
tective mechanisms may be classified as enzymatic and
Fig. (2). Oxidative stress signaling pathway and gene expression in sepsis. Abbreviations: IK, IB kinase complex; IRAK, interleukin-1
receptor-associated kinase; LPS, lipopolysaccharide; MyD88; myeloid differentiation protein 88; NEMO, Nf-B essential modifier; NF-B,
nuclear factor-B; Nox4, NADPH oxidase; TLR4, Toll-like receptor 4; TRAF6, tumor necrosis factor receptor-associated factor 6.
nonenzymatic antioxidants. Initially, catalase and glutathione
peroxidase are enzymes which can safely destroy peroxides
(especially hydrogen peroxide produced during the respira-
tory burst). Other free radical scavengers of crucial impor-
tance are constituted by non enzymatic molecules obtained
from the diet. The most important antioxidant in cell mem-
branes is -tocopherol (the main member of the vitamin E
family), but other dietary antioxidants exert an important
function in the improvement of immune efficiency. Table 1
summarizes the important role of selected vitamins and trace
elements on immune system functions.
3. DIETARY ANTIOXIDANTS AND IMMUNE SYS-
TEM
A natural antioxidant protects the body against free radi-
cals, which are highly reactive chemical agents produced
whenever our body undergoes the process of oxidation, e.g.
breathing. As previously mentioned, the immune system is
particularly sensitive to oxidative stress, which occurs when
an imbalance develops because of high ROS levels and/or
low antioxidant levels. Thus, increased oxidative stress in-
duced by a dietary deficiency in antioxidant nutrients would
be expected to affect host immune responses, leading to im-
pairment of host resistance to infectious microorganisms.
Therefore, oxidative stress has been implicated in the patho-
genesis of several microbial, parasitic and viral infections,
including hepatitis, influenza and acquired immunodefi-
ciency syndrome (AIDS) [9, 10], increasing the risk of mor-
bidity and mortality. It is obvious that one of the many func-
tions of natural antioxidants is to work against the formation
of cellular damage caused by free radicals in order to main-
tain an optimal host defense. Taking into account that ROS
are generated in vivo, organisms have evolved antioxidant
defence systems either to prevent the production of ROS or
to avoid ROS accumulation.
The excessive production of ROS, associated with in-
flammation, leads to a condition of oxidative stress. In states
of infection, antimicrobial activity of activated neutrophils
and macrophages involves ROS generation. Moreover, under
these circumstances, endothelial nitric oxide synthase (NOS)
is uncoupled resulting in reduced NO and increased O
2
-
pro-
duction, leading to systemic oxidative stress [11]. Therefore,
balance between ROS formation and ROS elimination is
crucial for maintaining homeostasis. Nevertheless, oxidative
stress may occur when this balance is disrupted by an exces-
sive generation of ROS, including superoxide, hydrogen
peroxide and hydroxyl radicals. Another reason by which
oxidative stress takes place is by inadequate antioxidant de-
fenses due mainly to changes in superoxide dismutase
(SOD), catalase, vitamins C and E, and reduced glutathione
(GSH). These actions may commonly occur during sepsis. In
this state, ROS may be generated by different sources, such
as the mitochondrial respiratory chain, the metabolism of
arachidonic acid, the protease-mediated enzyme xanthine
oxidase, granulocytes and other phagocytes activated by dif-
ferent factors (complement, bacteria, endotoxin, lysosomal
enzymes, etc.), other oxidases (mainly NADPH oxidase).
However, immune cells do not only produce ROS for the
microbicidal activity, but also they are especially sensitive to
external ROS, due to their high levels of polyunsaturated
fatty acids. Immune cells show an abnormal content of poly-
unsaturated fatty acids in comparison with other somatic
cells. Indeed, immune cells contain high levels of antioxidant
vitamins, presumably supplying protection against lipid per-
oxidation and immunosuppression, two risk factors caused
by high levels of polyunsaturated fatty acids [12]. Overall,
nutrients that affect the antioxidant status have important
effects on immune functions. For example, low plasma or
serum levels of vitamins C, E, carotenoids, selenium and
zinc are common in many human immunodeficiency virus
(HIV)-infected populations [9] and may contribute to the
pathogenesis and development of HIV infection through
increased oxidative stress and compromised immunity.
Therefore, an adequate intake of vitamins and trace elements
with antioxidant activities seems to be essential for an effi-
cient function of the immune system. Excellent reviews
about the effects of vitamins and trace elements are available
[13-15].
4. DIETARY ANTIOXIDANTS (VITAMINS AND
TRACE ELEMENTS): IMPACT ON INFECTION
Dietary micronutrients are indispensable components of
the antioxidant network. Therefore, adequate levels of mi-
cronutrients are necessary to a correct immune response
against infectious microorganisms, whereas micronutrient
deficiency leads to increased incidence of infection. Dietary
antioxidants of substantial importance for immune system
functions include vitamin C (ascorbic acid), vitamin E (com-
prising tocopherols and tocotrienols, of which -tocopherol
is the predominant and most active form) and -carotene. In
addition, minerals such as selenium, copper, zinc and iron
also act in the antioxidant network, primarily by serve as
cofactors for enzymes with antioxidant activity. In general,
trace elements do not act directly as antioxidants, but are
critical components of the antioxidant enzymes. Table 2 rep-
resents the most important studies focused on the impact
exerted by vitamins and trace elements on host resistance to
microorganisms.
4.1. Vitamins, Immune System and Host Resistance to
Infectious Microorganisms
High doses of both vitamins C and E exert a protective
function by reducing the adverse effects of oxidative stress
in sepsis. Vitamin C plays an important role in the protection
against oxidative damage particularly in leukocytes. The
main role of vitamin C is related to its function as an impor-
tant reductor (it is a powerful electron donor, reacting with
both O
2
-
and
OH radicals), but it is also involved in the

modulation of complex biochemical pathways, which are
crucial for the metabolism and function of immune cells.
Similarly, vitamin E has been described as the major chain-
breaking antioxidant in cellular membranes due to its ex-
tremely efficient antioxidant activity. This vitamin is essen-
tial for the maintenance of an appropriate immune response
to infection, especially in inflammatory cells. Finally, nu-
merous investigations have demonstrated that -carotene, a
potent quencher of singlet oxygen, acts as an antioxidant in
biologically relevant systems and it also affects several as-
pects of human immune system function.
Table 1. Antioxidants and Immune Functions
Dietary Antioxi-
dants (Exogenous)
Types of Dietary
Antioxidants
Immunological Effects References
1. Trace elements
Selenium
Increase of lymphocyte proliferation, expression of IL-2R and NK-cell function. Se-
supplementation is involved in enhancing Th1-type immune responses to a greater extent
than Th2-type responses. Deficiency promotes loss of immunocompetence (both cell-
mediated immunity and B-cell function may be impaired)
[63, 136,
137]
Copper
Adequate intake supports a Th1 response. Excessive supplementation reduces the activity of
phagocytic cells. Deficiency reduces antibody production, phagocytic activity, T-cell prolif-
eration, and B-cell numbers
[84]
Zinc
Cytosolic defense against oxidative stress. Increase of phagocytosis, NK cell activity and
DTH, antibody response. Augment of cytotoxic CD8
+
T lymphocytes
[93, 138,
139]
Iron
Differentiation and proliferation of T lymphocytes, NK cells, monocytes, and macrophages.
Deficiency reduces cytotoxic activity of phagocytes and proliferation of T-helper 1 cells, IL-
2 production, phagocytic activity and immunoglobulin levels
[109, 115,
116]
2. Vitamins
-carotene
Increase of mitogen-induced lymphocyte proliferation, cell-mediated cytotoxicity, and NK
cell activity. By contrast, it does not affect DTH, IL-2 production and lymphocyte subsets
[53, 54,
140]
Vitamin C
Increase of neutrophil chemotaxis, NK cell activity and T-lymphocyte proliferation. Aug-
ment of cytokine production and immunoglobulin synthesis
[141, 142]
Vitamin E
Deficiency reduces lymphocyte proliferation and phagocyte functions while supplementation
in healthy individuals increases lymphocyte proliferation, IL-2 production, NK cell activity,
and phagocytic functions
[143]
Table 2. Studies Reporting Antioxidant Function and Host Resistance to Microorganisms after Either Trace Elements or Vitamin
Supplementation or Deficiency
Dietary
Antioxidants
Microorganisms or
Diseases
Host Immune Resistance: Effects Species
Refer-
ences
Common cold
Reduction of duration and severity of symptoms. However, these conclu-
sions have absolutely not been clarified
Human [21, 22]
Candida albicans
Inability of macrophages to eliminate the pathogen. Increase of suscepti-
bility to microorganism in ex vivo studies
In vitro; Guinea
pigs
[29, 30]
Vitamin C
Helicobacter pylori
High doses had an inhibitory effect on bacteria colonization. Vitamin C
in the presence of classical treatment increased antimicrobial activity
Human [32, 33]
Influenza virus
Supplementation resulted in significantly lower viral titer on 2, 5, and 7
days post-infection as well as an increase of IL-2 and IFN- production
Mice [46, 47]
Herpes simplex virus
Adequate levels limited the herpes simplex virus encephalitis. Deficien-
cies impaired the course of infection, whereas supplementation did not
affect the progression of virus
Mice [50]
Trypanosoma cruzi Deficiency was associated with a reduction of T and B cell counts Rats [51]
Common cold
Supplementation reduced the incidence rate of common colds, but did
not affect the duration of this infection
Human [41]
HIV Reduction of viral load on 3 month of intervention Human [23]
Vitamin E
Hepatitis B HBeAg seroconversion after vitamin E treatment Human [43]

(Table 2) contd.
Dietary
Antioxidants
Microorganisms or
Diseases
Host Immune Resistance: Effects Species
Refer-
ences
HIV Increases number of NK cells, but did not affect CD4
+
population Human [55]
-carotene
HIV Reduction of T CD4+ subset and reduction of mortality Human [57,58]
Cryptosporidium parvum Increase of host susceptibility in selenium-deficient animals Mice [71]
Trichinella spiralis Supplementation plays an important role in the treatment of parasitoses Rats [70]
Candida albicans, Salmo-
nella typhimurium and
Staphylococcus aureus
Deficiency impaired neutrophil and macrophage functionality to elimi-
nate this pathogen. Selenium deficiency did not affect to neutrophil in the
elimination of S. typhimurium or S. aureus
Rats, Mice [69, 72]
Listeria monocytogenes
Deficiency impaired systemic innate immune response to L. monocyto-
genes infection
Mice [71]
Coxsackievirus B
Coxsackie B virus mutates to a cardiotoxic form in selenium-deficient
hosts (Keshan disease)
Mice and hu-
mans
[73]
Influenza virus
Selenium-deficient animals were more susceptible to influenza virus
infection
Mice [75]
Hepatitis B or C viruses Reduced the risk of hepatocarcinoma caused by virus infection Human [76, 77]
Selenium
HIV
Low plasma selenium levels were associated with a significant increase
of death risk, as well as mycobacterial infections
Human [78, 79]
Salmonella typhimurium Deficiency produced higher mortality rates than control animals Rats [85]
Copper
Trypanosoma lewisi
Copper deficiency was responsible for causing severe depression in the
primary and secondary antibody responses
Rats [86]
Listeria monocytogenes
Zinc-deficient animals showed thymic atrophy, reduced DTH and im-
paired lymphocyte response
Rats [94]
Salmonella enteritidis
Increased in vitro phagocytosis, but did not affect number of mononu-
clear cells
Turkeys [95]
Mycobacterium tuberculosis
Zinc-deficient animals had fewer circulating T cells and reduced tubercu-
lin hipersensivity
Guinea pigs [96]
Candida albicans
Increased host resistance against this pathogen, because it potentiated T-
lymphocyte and macrophage functions
Mice [144]
Trypanosoma cruzi
Increase of peritoneal macrophages, as well as IFN- and NO production
after zinc supplementation
Rats [145]
Plasmodium falciparum Reduction of morbidity after zinc supplementation
Human (pre-
school children)
[102]
HIV Increase of CD4
+
counts and a reduction of opportunistic infections Human [146]
Pneumonia
Reduction of incidence. Supplementation with zinc and selenium signifi-
cantly increased the humoral response in elderly individuals after vacci-
nation, increased the number of patients without respiratory infections
Human
[101,
105]
Zinc
Common cold No evidence of effective action Human [104]
Salmonella typhimurium Severe deficiencies enhance defenses against infection Rats [111]
Iron
Sreptococcus pneumoniae Severe deficiencies increase mortality Rats [112]
4.1.1. Vitamin C
Vitamin C (ascorbic acid) is defined as the major water-
soluble cytosolic chain-breaking antioxidant that plays an
important role in the host defense against oxidative damage,
especially in leukocytes. In addition, vitamin C provides
important antioxidant protection to plasma lipids and lipid
membranes and can neutralise phagocyte-derived oxidants
released extracellularly, thereby preventing oxidant-mediated
tissue damage, especially in the sites of infection [16, 17].
Natural vitamin C possesses immunostimulatory, anti-
inflammatory, and anti-allergic properties. It is essential to
promote optimal migration of neutrophils and macrophages
to infection sites [18]. Biological effects of vitamin C appear
to affect most aspects of immune functions, because concen-
trations of this vitamin in the plasma and leukocytes rapidly
decline during infections. For this reason, it is believed that
ascorbic acid reduces the incidence of cold; however, this
event has not been clearly demonstrated. Early studies have
reported that the moderate intake of ascorbic acid seems to
reduce the duration of episodes and the severity of symptoms
of common cold infections [19, 20]. Other studies have re-
ported a no effect of vitamin C administered in women, but
the incidence of colds was significantly reduced in school-
children and students after vitamin C administration [21]. On
the contrary, other investigations suggest that vitamin C sup-
plementation significantly reduced the frequency of the
common cold, but had no apparent effect on the duration or
severity of the common cold [22]. Based on these results, it
is important to note that there was no substantial evidence to
support the claim that taking high doses of vitamin C de-
creases the incidence and severity of colds. However, the
possibility of a beneficial effect of vitamin C on viral infec-
tions cannot be totally discarded. Irrespective of the contra-
dictory studies, this topic generates an important matter of
debate, which has not been clarified yet. In this context, it is
important to underline other experimental observations that
demonstrate a reduction of plasma ascorbate in subjects with
HIV infection, which indicates that such individuals have
greater vitamin C requirements than non-infected persons
[23]. In addition, high intakes of vitamin C were associated
with a lower risk of progression to AIDS in an observational
study of US men, reducing the severity of HIV disease [24].
Vitamin C was found to improve components of the hu-
man immune system, such as antimicrobial and NK cell ac-
tivities, lymphocyte proliferation, chemotaxis, production of
IFN, gene expression of monocyte adhesion molecules and
delayed-type hypersensitivity (DTH) [25-27]. It is clear that
neutrophil function is altered in the presence of vitamin C
exerting anti-inflammatory activities, because vitamin C
attenuates the activation of the transcription factor NF-B
[28]. While vitamin C supplementation might be advanta-
geous for inhibiting neutrophil-induced tissue damage in
individuals suffering from ischemia and chronic inflamma-
tory disease, perhaps it would impair the ability of neutro-
phils to destroy and to eliminate pathogens in healthy per-
sons or in those susceptible to infection (immunocom-
promised patients).
In vitro studies have demonstrated as neutrophils were
unable to phagocytise Candida albicans when high concen-
trations of vitamin C were added [29]. Similarly, studies in
animals have demonstrated that low levels of vitamin C in-
crease the susceptibility to candidiasis [30]. Conversely, vi-
tamin C has showed antimicrobial activity against Helico-
bacter pylori against both in vitro and in vivo. The minimal
inhibitory concentration values of vitamin C for 64 H. pylori
strains were tested and vitamin C exhibited an inhibitory
effect on growth. The in vivo experiment performed in ani-
mals suggested that a high dose of vitamin C had an inhibi-
tory effect on H. pylori colonization in the animal stomachs
[31]. In addition, a recent study has determined that the ad-
ministration of both vitamin C and E together with antimi-
crobial therapy promotes an effective eradication of H. py-
lori. Indeed, the antimicrobial activity exhibited against this
pathogen is higher than that shown by antimicrobial drugs
administered in the absence of vitamins [32]. Recently, it has
been demonstrated that vitamin C with the dose of 500
mg/day when is added to treatment regimen of amoxicillin,
metronidazole and bismuth may significantly increase H.
pylori eradication rate [33]. Other studies with human sub-
jects reported a significantly lower incidence of pneumonia
in vitamin C supplemented groups, suggesting that under
certain conditions, vitamin C might affect vulnerability to
pneumonia [34, 35]. Finally, topical application of an ascor-
bic acid solution in patients infected with herpes simplex
virus reduced the duration of the lesions and viral shedding
[36].
4.1.2. Vitamin E
Vitamin E may be described as the major chain breaking
lipid soluble antioxidant that reduces damage to lipid mem-
branes due to the formation of ROS during infections. There-
fore, vitamin E exerts an important role in maintaining the
cell membrane integrity, and in preventing lipid peroxidation
by scavenging free radicals. Vitamin E is constituted by a
family of tocopherols and tocotrienols, of which -
tocopherol is the most biologically active and the second
most abundant in foods. Vitamin E is crucial for the im-
provement of immune functions: it increases lymphocyte
proliferation, IL-2 production, NK cell activity, and phago-
cytic functions by alveolar macrophages. Consequently, vi-
tamin E causes an increased resistance against infectious
microorganism suggesting that higher vitamin E intake in-
duces a Th1 cytokine mediated response and suppresses the
Th2 response [37], therefore, this is one of the mechanisms
through which vitamin E provides protection against intra-
cellular growth pathogens. In addition, oxidative stress is
increased in AIDS and can induce apoptosis in T lympho-
cytes by two reasons: (i) a deficiency in antioxidant mole-
cules, and (ii) low levels of bcl-2 protein (which exerts an
anti-apoptotic activity). Hence, in HIV-infected patients
there is a significant increase of CD4
+
T lymphocyte apopto-
sis that correlates with antioxidant and vitamin E deficiency
[38, 39].
The studies of the effects of vitamin E on humans are
limited and the most part of them restricted to aged individu-
als. A double blind, placebo-controlled investigation deter-
mined a favourable effect on incidence and severity of acute
respiratory tract infections in elderly after daily multivita-
min-mineral supplementation at physiological dose and 200
mg of vitamin E [40]. By a strict contrast, a randomized
double-blind study, 617 people aged over 65 received either
a placebo or 200 IU of vitamin E daily for 1 year. The main
outcomes of this study were a reduction of the risk for ac-
quiring respiratory infections in elderly. Significantly fewer
vitamin E-supplemented subjects acquired one or more res-
piratory infections. The vitamin E-treated group also had
fewer days with common cold per personyear compared to
the placebo group, but the difference did not reach statistical
significance. In particular, vitamin E supplementation re-
duced the incidence rate of common colds, however, a non
significant reduction in the duration of colds was also ob-
served in this study [41]. HIV infections as well as opportun-
istic infections (highly frequent in these patients) can pro-
mote high levels of free radicals and oxidative stress. Over-
all, these observations suggest that increasing vitamin E in-
take above habitual levels might enhance immune function
and improve resistance against pathogen microorganisms,
and that vitamin E supplementation might be particularly
beneficial in the elderly. The presence of these free radicals
has been related to an accelerated progression toward AIDS
[42]. Patients with HIV infection and AIDS will have lower
levels of antioxidants, including vitamin E, leading to vita-
min deficiency. In a small, randomized placebo-controlled
study, HIV-infected patients who received supplements of
both vitamin E (800 IU daily) and vitamin C (1000 mg daily)
for 3 months had a considerable diminution in lipid peroxi-
dation and a significant reduction of viral load [23]. Vitamin
E has also been used in children suffering from chronic
hepatitis B. Results showed that vitamin E (supplementation
with 200, 400 or 600 IU of vitamin E) may promote HBeAg
seroconversion, which is defined as the loss of HBeAg [43].
Research in murine AIDS using a 15-fold increase in dietary
vitamin E demonstrated progressive normalization of im-
mune parameters such as mitogen-stimulated T cell prolif-
eration, increase of NK cell activity, and reduction of TNF-
production, which are highly altered in AIDS [44]. Other
animal studies have revealed that long-term vitamin E sup-
plementation is effective in lowering viral titer, increasing
IL-2 and IFN- production, and preventing decreased food
intake and weight loss following influenza infection in aged
mice [45-47]. However, providing megadose (approximately
300 mg/day) of vitamin E for three weeks depressed the bac-
tericidal activity and proliferation of peripheral leukocytes in
humans [48] and reduced vaccine titers in animals (150
mg/kg) [49]. Adequate levels of vitamin E are important in
limiting herpes simplex virus encephalitis pathology,
whereas vitamin E deficiency impairs the course of infec-
tion. Nevertheless, it is important to note that vitamin E sup-
plementation does not improve symptoms in comparison
with vitamin E-adequate mice [50]. Vitamin E deficiency
also contributes to an enhancement of pathology in Trypano-
soma cruzi-infected rats by a reduction of the numbers of
CD45RA
+
CD3
-
B-cells and CD3
+
CD4
+
T-lymphocytes [51].
4.1.3. -Carotene
-carotene is the predominant source of the essential nu-
trient, vitamin A (retinol and its esters). In fact, -carotene
has traditionally been considered as a source of vitamin A
with this exclusive function. However, several studies have
shown that carotenoids can enhance immune functions inde-
pendently of any provitamin A activity. There are relatively
few studies to delineate completely the specific effects on
host defense of -carotene from its prior conversion to vita-
min A. Several investigations have examined the effect of -
carotene on immune function by measuring changes in the
numbers of lymphocyte subpopulations, particularly in the
counts of T-helper (CD4
+
) lymphocytes and NK cells, but
long-term effectiveness has not been reported [52]. Never-
theless, other investigations have reported that -carotene
supplementation was associated with higher NK cell activity,
but no change in DTH, lymphocyte proliferation, IL-2 pro-
duction and lymphocyte subsets [53, 54]. These experimen-
tal observations, especially the potential for increasing the
numbers of CD4
+
cells, suggest that -carotene might be
useful as an immunoenhancing agent in the treatment of HIV
infection. Hence, -carotene is able to increase NK cell
number, but does not affect the CD4 population in HIV-
infected patients [55]. Taking into account that septic pa-
tients present inadequate concentrations of -carotene [56],
different studies have determined that low concentrations of
serum vitamin A and -carotene in HIV-infected patients
decrease CD4
+
lymphocyte counts and increase mortality.
Therefore, HIV-infected individuals, who ingest moderately
increased amounts of dietary -carotene have a diminished
risk of dying or developing AIDS [57, 58]. However, ad-
verse effects [59] or no effects [60] have also been reported
after -carotene supplementation in patients with normal
baseline serum levels of this bioactive component.
4.2. Trace Elements, Immune System and Host Resis-
tance to Infectious Microorganisms
All types of cells (but particularly immune cells) require
an adequate supply of trace elements for the structure and
function of metalloproteins that contribute to maintain proc-
esses such as i) energy production (e.g., copper for cyto-
chrome c oxidase in the mitochondrial electron-transport
chain; iron for cytochromes a, b and c, NADH and succinate
dehydrogenases), ii) protection against ROS (e.g., selenium
for glutathione peroxidases, copper and zinc for superoxide
dismutase, and iron for catalase), and iii) protection against
infection (trace elements are also necessary for the activity of
a wide variety of enzymes that directly participate in host
defense mechanisms). Consequently, essential trace elements
are required for the differentiation, activation and perform-
ance of numerous functions of immune cells, but the precise
roles of these inorganic micronutrients in these processes
have not been totally defined. In addition, trace elements
compete with each other in terms of absorption, cellular up-
take, transport, etc. and are required as cofactors for vitamins
that regulate immune response to infection.
4.2.1. Selenium
Selenium acquires a crucial importance in balancing the
redox state of the cell and removing ROS. The antioxidant
activity of this element is determined by glutathione peroxi-
dase, the enzyme that recycles glutathione, which depends
on the presence of selenium for exerting its antioxidant ac-
tivity [61]. The antioxidant properties attributed to selenium
are able to produce a protective barrier against free radicals
contributing to improve the intracellular digestion of phago-
cyted bacteria. A lack of glutathione peroxidase produces a
damage of lysosomal membranes by lipid hydroperoxides,
leading to the release of various hydrolytic enzymes into the
cytoplasm. In combination with vitamin E, selenium appears
to act as an oxidant scavenger and protects against oxidative
damage [62]. Individually, selenium increases lymphocyte
proliferation, expression of the high-affinity IL-2R, cytolytic
T lymphocyte tumor destruction, and NK-cell function in
humans [63], enhancing resistance to infections through
modulation of interleukin production and subsequently the
Th1/Th2 response [64]. The mechanism appears to be
closely related to the ability of selenium to upregulate the
expression of receptors for IL-2 on the surface of activated
lymphocytes and NK cells. This event favours the interaction
of this cytokine with its respective receptors [65]. A defi-
ciency in selenium has widely been described to affect the
immune system and to have an effect on the ability to control
the infection [66, 67]. Thus, selenium deficiency is involved
in a higher host susceptibility to Cryptosporidium parvum
infection, because this deficit decreases immune response. In
other words, selenium appears to play an important role for
preventing C. parvum infection [68]. Similarly, deficiency of
selenium in either rats or mice impairs the ability of neutro-
phils and peritoneal macrophages to kill Candida albicans
organism in vitro [69]. By contrast, selenium supplementa-
tion at low doses may prevent the formation of free radicals
and lipid peroxidation processes in trichinellosis, acquiring a
considerable importance in the treatment of diseases corre-
lated with oxidative stress generation, especially parasitoses
[70]. Similarly, bacterial infections have demonstrated that
the ability of the host to elicit a rapid recruitment and activa-
tion of systemic innate immune response to infection was to
a certain extent compromised under conditions of selenium
deficiency increasing the persistence of L. monocytogenes in
the intestine and mesenteric lymph nodes compared to the
selenium-adequate mice [71]. In contrast, killing of Salmo-
nella typhimurium and Staphylococcus aureus by neutrophils
was unaffected by selenium-deficiency [69, 72]. Undoubt-
edly, one of the most interesting effects in the relationship
among selenium deficiency, immune system and viral patho-
genesis has been focused on an endemic disease in China,
which is called Keshan disease, a cardiomyopathy character-
ized by necrotic lesions throughout the myocardium accom-
panied by cellular infiltration and calcification. However, the
deficiency in selenium did not appear to entirely explain the
epidemiological pattern of the disorder, because an infection
produced Coxsackie B viruses were commonly identified
using both blood and tissue samples from patients diagnosed
with this pathology. Thus, it appears that both a deficiency in
selenium together with a coxsackievirus infection results in
Keshan disease, since coxsackie B virus is able to mutate to
a cardiotoxic form in selenium-deficient hosts. Indeed, an
interesting investigation with a murine model has demon-
strated that selenium-supplemented animals and experimen-
tally infected with a strain of coxsackievirus B3 did not pro-
duce a development of myocarditis [73]. In critically ill pa-
tients, meta-analysis show that trace elements and vitamins
that support antioxidant function, particularly selenium, ei-
ther alone or in combination with other antioxidants are safe,
and may be associated with a reduction in mortality in these
individuals [74].
Similarly, selenium-deficient mice were more susceptible
to influenza virus infection than selenium-adequate mice
[75]. Viruses may be capable of capturing the selenium
available for the host by incorporating selenium into viral
selenoproteins, thereby reducing the ability of the host to
develop an effective immune response [65]. Selenium has
been demonstrated to be protective against infections caused
by either hepatitis B or hepatitis C viruses, because reduces
the risk of hepatocarcinoma promoted by these viruses [76,
77]. Selenium also plays a critical role in HIV-infected pa-
tients. Several studies have determined that low plasma sele-
nium levels were associated with a 10-fold higher risk of
death compared with individuals with normal status [78]. In
addition, low plasma selenium was also associated with a 3-
fold increased risk for development of mycobacterial disease
in these patients [79]. In fact, it has been described a pro-
gressive decline in plasma selenium in parallel with the loss
of CD4
+
T cells in HIV infection [80]. Adequate levels of
selenium in HIV-infected patients allow an effective cellular
immunity, and the host cells will be less likely to die by
apoptosis induction. Under low selenium levels, the augment
of oxidative stress and apoptosis induction are able to acti-
vate the virus, which replicate at higher rates to escape from
the cell, leading to increased pathogenic effects [81, 82].
4.2.2. Copper
Copper deficiency impairs both the innate and acquired
arms of the immune system suppressing the proliferation of
activated T cells and the production of pro-inflammatory
cytokines such as IL-1, IL-2, and TNF. In addition, copper
deficiency reduces phagocytic activities, as well as the num-
ber of mature neutrophils in peripheral blood [83]. Similarly,
copper deficiency is also related to a reduction of mononu-
clear phagocytic activities, which compromises the innate
immune defence system and contributes to greater suscepti-
bility to infections [84]. In fact, early studies demonstrated
the importance of mononuclear phagocytes in copper-
deficient rats infected with Salmonella typhimurium. These
animals showed higher mortality rates and shorter survival
than control animals [85]. In addition, copper deficiency is
responsible for a significant reduction of in the primary and
secondary antibody responses and the duration of infection
was longer than in uninfected animals [86].
A reduction in candidacidal activity of peritoneal macro-
phages has also been detected in marginally copper-depleted
rats when compared with peritoneal macrophages from cop-
per-adequate rats [87].
Human studies showing the effects of copper on the im-
mune response are limited due mainly to the lack of sensitive
and specific biomarkers that allow to evaluate copper defi-
ciency status. Copper supplementation has also been shown
to increase numbers of neutrophils in peripheral blood and to
reduce the incidence of respiratory tract infections in infants
recovering from marasmus, who were neither anaemic nor
neutropaenic [88]. By contrast, a recent study has demon-
strated that high intakes of copper reduced significantly the
number of circulating neutrophils, IL-2 receptors in serum
and the titer of antibody against the Beijing strain of influ-
enza virus. Immunization supplemented individuals caused a
14-fold increase in antibody titer against this influenza
strain, whereas the increase was 47-fold in control subjects.
The results from this study indicate that under highly con-
trolled conditions, long-term high copper intake affects sev-
eral indexes of immune function. Nevertheless, the physiol-
ogic implications of these changes are still unknown [89].
4.2.3. Zinc
Zinc plays a relevant role as antioxidant in the defence
system, and it is essential for optimal immune function and
protection from infections, especially in the elderly. The con-
tribution of zinc is crucial for the activity of superoxide dis-
mutases and participates in T-cell division, maturation and
differentiation. It is clear that zinc is involved in many as-
pects of immunological functions; therefore, adequate zinc
amounts play a pivotal role in maintaining the integrity of
the immune system [90, 91]. Zinc deficiency results in a
marked atrophy of the thymus involving an increase in lym-
phopenia. Consequently, zinc is essential for the integrity of
the thymus gland. Similarly, zinc is crucial for normal de-
velopment and adequate function of cells mediating nonspe-
cific immunity such as NK cells and neutrophils. Zinc defi-
ciency affect development of acquired immunity by prevent-
ing several functions of T lymphocytes such as activation,
Th1 cytokine production, as well as B lymphocyte functions
such as immunoglobulin G synthesis. Dietary zinc restriction
is associated with decreased secretion of IFN-, TNF- and
IL-2. These observations clearly indicate that zinc plays an
important role in maintaining the appropriate balance be-
tween cell-mediated and humoral immune response by regu-
lating patterns of cytokine secretion [92]. In addition, the
macrophages also are adversely affected by zinc deficiency,
which can dysregulate elimination of foreign agents by
phagocytosis and cytokine production. It is obvious that
these factors are deleterious to antibody and cell mediated
responses, leading to an enhancement of opportunistic infec-
tions and an increase of morbidity and mortality percentages
[93]. For these reasons, zinc deficiencies are characterized
by promoting an increased susceptibility to a diverse variety
of infectious agents, including Listeria monocytogenes [94],
Salmonella enteritidis [95], Mycobacterium tuberculosis [96]
and herpes simplex virus [97]. In patients suffering from
AIDS, a zinc deficiency has been observed (as a result of
decreased appetite, malabsorption and increased losses of
endogenous zinc due to diarrhea and recurrent infections),
and a disease progression as well as a depressed mitogenic
reponse have been described [98]. However, these changes
were partially reversible by zinc supplementation [99]. In a
strict contrast, an important study reported that zinc supple-
mentation in patients with HIV induces a more rapid pro-
gression of the disease [58], due probably to an excessive
zinc administration, which may stimulate HIV. Hence, these
observations indicate the need to carefully consider therapeu-
tic options, and immune status should be evaluated after as-
serting a beneficial role of zinc supplementation in these
patients [100].
Several lines of evidence have also reported that zinc
supplementation decreases the severity, duration, and inci-
dence of diarrhea and decreases the incidence of pneumonia
[101]. Consequently, several investigations have emphasized
the antimicrobial action of zinc. The relatively low frequency
of urinary tract infections in men may be attributed, at least
in part, to the high zinc levels in semen [102].
In addition to vitamin C, zinc supplements were also
shown to decrease the duration of the common cold [103].
Thus, the effect of zinc on the common cold may be associ-
ated with the increased zinc concentrations in the nasal mu-
cosa, which may affect the conformation of the binding site
between the virus and intercellular adhesion molecule-1
(ICAM-1) [102]. By a strict contrast, other studies have also
concluded that there was no convincing and consistent evi-
dence supporting zinc to be effective in the treatment of the
common cold [104].
In a randomized, double-blind, placebo-controlled inter-
vention study, low-concentration zinc and selenium supple-
mentation (constituted by 20 mg as zinc sulfate and 100 mg
as selenium sulfide) over a 2-year period significantly in-
creased the humoral response in elderly individuals after
vaccination. The number of subjects without respiratory in-
fections during the study period was also found to be higher
in the group that received trace elements. While this study
suggests that zinc may exert a protective effect against respi-
ratory tract infections, contributions from other nutrients in
the administered mixture cannot be discarded [105]. There-
fore, a recent review reports that low zinc status impairs im-
mune function, impairs resistance to pathogens, and is asso-
ciated with increased incidence and duration of pneumonia
resulting in augmented use and duration of antimicrobial
treatment, and increased mortality in the elderly [106].
4.2.4. Iron
Until now, deficiencies in trace elements are responsible
for causing an increase of morbidity and mortality due to the
risk of infection. However, iron deficiency may be protective
to malaria and Yersinia infections, whereas iron overload
may predispose to infection by supplying necessary amounts
of iron for the development and growth of bacteria [107] or
by enhancing the rate of progression of HIV disease, and
decrease survival [108]. Therefore, the role of iron supple-
mentation in the immune system or in the incidence of infec-
tion is controversial and some studies doubt about the safety
of this intervention [109].
Adequate amount of iron is vital to numerous immune
functions, including the differentiation and proliferation of T
lymphocytes, NK cells, monocytes, and macrophages. Iron
interacts with cell-mediated immune effector pathways, and
modulates cytokine activities. Iron is able to modify the gen-
eration of ROS by iron-dependent enzymes, which are nec-
essary to elimination of pathogens. Thus, iron is required for
myeloperoxidase activity, which participates in the killing
process of bacteria by neutrophils through the formation of
highly toxic hydroxyl radicals. In this context, it is important
to note the identification of an iron-related phagocyte protein
called natural-resistance associated macrophage protein-1
(NRAMP-1), which is located into the phagolysosomal
membrane of macrophages, monocytes and neutrophils. This
protein transports divalent metals, including Fe
++
, and pro-
vides protection against intracellular microorganisms, such
as Leishmania, Mycobaterium and Salmonella [110]. The
expression of this protein depends on host cell iron status
and it accentuates the importance of iron in the study of hu-
man infectious disease susceptibility. In fact, experimental
and in vitro animal studies suggest that growth of intracellu-
lar organisms such as plasmodia, mycobacteria and invasive
salmonellae, may be enhanced by iron therapy. By contrast,
iron deficiency could have a protective effect in malaria,
HIV disease and tuberculosis [109]. In addition, early ex-
perimental studies of infectious challenge have demonstrated
that severe deficiencies enhance defenses in animal models
against invasive Salmonella typhimurium (whereas mild de-
ficiency impaired them) [111] or against Streptococcus
pneumoniae compared with controls [112]. Effects in iron
deficiencies are early known. A study conducted by Baggs et
al., 1973 [111] found more viable extracellular and intracel-
lular bacteria in the macrophages and intestinal walls of iron-
deficient rats infected with Salmonella, whereas in animals
maintaining optimal levels of iron, the count of viable bacte-
ria was lower. In humans, a prospective study in children
from Papua New Guinea describes the possible evidence for
a protective effect of low iron stores at birth on subsequent
malarial morbidity. Infants with lower hemoglobin levels at
birth were less likely to have malaria and to be admitted dur-
ing the first year of life. Since birth hemoglobin is the main
iron source during this period, this interrelation may suggest
that iron deficiency protects from malaria and from other
infections [113, 114] .
Therefore, competition between host and microorganism
for iron may constitute a crucial episode for the development
of many infections. Indeed, iron deficiency impairs the T-
cell response and IL-2 production, as well as reduces phago-
cytic activity and immunoglobulin levels [115, 116]. Macro-
phages do not directly acquire iron, therefore, they obtain
this trace element from transferrin via endocytosis of trans-
ferrin receptor-bound iron, and through erythrocyte phagocy-
tosis. In iron deficiency subjects, neutrophils (which are de-
pendent on surface expression of transferring receptor) have
reduced the activity of myeloperoxidase, and as a result these
immune cells have diminished the migratory activity to sites
of infection. Consequently, intracellular killing of bacteria
and elimination of microorganism is significantly impaired
due to iron deficiency. Similarly, NK cells are sensitive to
iron deficiency and show a lower cytotoxic activity prolifera-
tion [117, 118]. Other studies indicate that iron supplementa-
tion causes an increased rate of malaria, pneumonia, and
diarrhea [109], although the occurrence of malarial parasi-
taemia was not significantly affected by iron administration
[119]. It is clear that insufficient data are available on iron
supplementation in relation to HIV or tuberculosis outcomes
for conclusions to be drawn about possible benefits or risks.
In spite of the fact that iron exerts important modulatory ef-
fects on immune functions, a clinically important relation-
ship between states of iron deficiency and susceptibility to
infections remains controversial.
5. OTHER NATURAL ANTIOXIDANTS CONTAINED
IN FOODS: A BRIEF DESCRIPTION
Polyphenols are phytochemicals which are found in food
substances produced from plants. Polyphenols are separated
from essential micronutrients because a deficiency state has
not been detected, however these chemicals play an impor-
tant immunomodulatory role [120]. Polyphenolic compo-
nents as (3,4-dihydroxyphenyl)ethanol (also termed hy-
droxytyrosol) have been related to exert a protective effect
against those intestinal pathologies whose etiology has been
related to ROS generation, in particular those characterized
by changes in epithelium permeability such as inflammatory
diseases [121]. This dietary antioxidant may be found in
olive oil (which is an important source of vitamins [e.g. -
tocopherols] and polyphenolic antioxidants, and has a bal-
anced ratio of monounsaturated and polyunsaturated fatty
acids). Olive oil has beneficial effect on the human health
and it is implicated in the resolution, attenuation or preven-
tion of diverse pathologies. Among them, olive oil is charac-
terized by modulating immune system functions [122, 123]
and it is involved in the prevention of cellular oxidative
stress and inflammation due mainly to the presence of anti-
oxidants [124]. These regulatory functions in the immune
system appear to be involved in an increase of host resis-
tance to microorganisms after administration of diets con-
taining olive oil [123]. Studies in vitro have suggested that
phenolic components from olive oil possess radical scaveng-
ing activity at least as strong as that of other relevant dietary
antioxidants, such as ascorbic acid and -tocopherol [125].
Phenolic components from olive oil such as oleuropein
added to murine macrophages together with a bacterial
lipopolysaccharide increase the functional activity of macro-
phages in the production of the bactericidal and cytostatic
factor nitric oxide [126].
Tea has also been traditionally consumed to eliminate
toxins, and to improve resistance to diseases. Tea consists of
numerous active components that may contribute to modu-
late immune system. The main active constituents of tea in-
clude a high content of polyphenols called flavonoids (cate-
chins, theanine, etc) that appear to be involved in the immu-
nodulating activities of tea. Tea has been shown to inhibit
the growth of bacteria responsible for upper respiratory tract
infections [127, 128]. In addition, tea polyphenols and ex-
tracts delay or inhibit the growth of a wide variety of patho-
genic strains of Enterobacteriaceae [128], without affecting
Lactobacilli growth.
Curcumin is an anti-inflammatory active principal ingre-
dient of the curry spice turmeric with antioxidant properties.
In a clinical trial, the administration of moderate amounts
(2g/day) of curcumin to 18 HIV-infected patients for ap-
proximately 29 weeks resulted in a significant increase in the
CD4 and CD8 lymphocyte counts as wells as B cells,
whereas a no alteration in the number of macrophages was
detected [129]. The oral administration of curcumin below
the recommended dietary supplement dose, activates the
nuclear receptor peroxisome proliferator-activated receptor-
(PPAR-) in mice, modulates the inflammatory and anti-
inflammatory immune response, and influences adaptive
immunity to Leishmania donovani [130].
The main polyphenol contained in red wine is resveratrol,
which has shown a relevant immunomodulatory activity
[131, 132], although the exact mechanism by which resvera-
trol exerts the immunomodulatory activity has not clearly
been defined, but it appears to inhibit cell proliferation, cell-
mediated cytotoxicity, and cytokine production [132]
through the inhibition of NF-B activation [131]. As a result
of its immunomodulatory properties, it has been demon-
strated that resveratrol protects mice from infection with
herpes simplex viruses [133, 134] and exerts antiviral activ-
ity against varicella-zoster virus in vitro [135].
6. CONCLUSIONS AND FUTURE PERSPECTIVES
Antimicrobial host defenses are strongly dependent on
induced oxidant stress to the microorganisms responsible for
infection. In addition, uncontrolled oxidative reactions are
extremely harmful to normal tissues, and result in chemical
damage to proteins, lipids and nucleic acids. Consequently,
the immune system of mammals is extremely sensitive to
oxidative damage and host resistance to infectious microor-
ganism is affected by an inadequate balance of oxidative
stress. Hence, it is necessary to regulate the reactions which
release free radicals.
Adequacy or deficiency in the micronutrient status of
both animals and humans affects profoundly their immuno-
competence. Among the different micronutrients, antioxidant
vitamins (vitamin C and E) and -carotene as well as some
trace elements (such as selenium, copper, zinc or iron) are
particularly required at appropriate intakes for the regulation
of immune system functions and host defense against infec-
tious microorganisms. Commonly, deficiencies in dietary
antioxidants predispose and aggravate the infection. Low
plasma levels of vitamins C or E and trace elements such as
selenium and zinc contribute to an increase of oxidative
stress in HIV-infected patients, leading to an impairment of
immunocompromised state. However, overdoses of other
micronutrients such as iron favour the development of sev-
eral infectious microorganisms.
Deficiencies in vitamins and minerals increase the impact
of microbial infections in both animals and humans. In fact,
deficiencies in either vitamin C or E reduce antibody levels
and phagocytosis. Deficiencies in trace elements such as
selenium, copper iron and zinc reduce T-cell proliferation,
whereas selenium deficiency promotes a reduction of cyto-
kine synthesis. Further research needs to examine the inter-
action between different antioxidant nutrients and to estab-
lish the levels of intake required in different groups of the
population to optimise immune response, because reduction
in several of these micronutrients have been related to in-
crease the vulnerability in clinical infection, and several ran-
domized trials suggest that supplementation with one or
more of these micronutrients may reduce susceptibility or
ameliorate the effect of various types of infection.
Further investigations needs to be performed to evaluate
the interaction between different antioxidant nutrients and to
establish the levels of supplementation necessary to optimise
immune responsiveness in different population groups (for
example older people, smokers) characterized by different
immunological response depending on their particular state.
In addition, it is required more emphasis to examine the ef-
fects of enriching the diet with antioxidants via real food-
stuffs rather than by supplementation. Indeed, when these
processes are clarified and completely understood, we may
regulate immune status, improve health and prevent, or at
least, minimize the effects of numerous diseases.
ABBREVIATIONS
AIDS = Acquired immunodeficiency syndrome
DTH = Delayed type hypersensitivity
GSH = Reduced glutathione
HIV = Human immunodeficiency virus
ICAM-1 = Intercellular adhesion molecule-1
IFN- = Interferon-
IL = Interleukin
NF-B = Nuclear factor B
NK = Natural killer
NO = Nitric oxide
NOS = Nitric oxide synthase
NRAMP-1 = Natural-resistance associated macrophage
protein-1
PPAR- = Peroxisome proliferator-activated receptor-
RNS = Reactive nitrogen species
ROS = Reactive oxygen species
SOD = Superoxide dismutase
TNF = Tumor necrosis factor
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Received: March 10, 2010 Accepted: June 03, 2010

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1752 Current Topics in Medicinal Chemistry, 2011, 11, 1752-1766

1568-0266/11 $58.00+.00 2011 Bentham Science Publishers Ltd.

OH) and hydro-

OH radicals), but it is also involved in the

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