Microbial Pathogenesis 137 (2019) 103714

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Microbial Pathogenesis
journal homepage: www.elsevier.com/locate/micpath

Diet and nutrition: An important risk factor in leprosy T

a,∗∗ b c d e
Ved Prakash Dwivedi , Arindam Banerjee , Indraneel Das , Aparajita Saha , Malabika Dutta ,
Bhavya Bhardwaja, Saptarshi Biswasf, Debprasad Chattopadhyayg,8,∗
a
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
b
Rafi Ahmed Dental College, Govt of West Bengal, Moulalai, Kolkata, 7600014, India
c
Declibac Technologies Private Limited, 24 B, Lake Road, Kolkata, 700 029, India
d
Nutri-Diet Kolkata, 34A Charu Avenue, Kolkata, 700033, India
e
Department of Dietetics, Kothari Medical Center, 8/3 Alipore Road, Kolkata, 700027, India
f
Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
g
ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi, 590010, India
8
ICMR-Virus Unit, ID & BG Hospital, General Block 4, 57 Dr Suresh C Banerjee Road, Beliaghata, Kolkata, 700010, India

A R T I C LE I N FO A B S T R A C T

Keywords: Leprosy, once considered as poor man's disease may cause severe neurological complications and physical
Leprosy disabilities. Classification of leprosy depends upon the cell mediated and humoral immune responses of the host,
Multi-drug therapy from tuberculoid to lepromatous stage. Current therapy to prevent the disease is not only very lengthy but also
Nutrition consists of expensive multiple antibiotics in combination. Treatment and the duration depend on the bacillary
Immune responses
loads, from six months in paucibacillary to a year in multibacillary leprosy. Although as per WHO re-
Cytokines
Cell mediated immunity
commendations, these antibiotics are freely available but still out of reach to patients of many rural areas of the
Humoral immunity world. In this review, we have focused on the nutritional aspect during the multi-drug therapy of leprosy along
with the role of nutrition, particularly malnutrition, on susceptibility of Mycobacterium leprae and development
of clinical symptoms. We further discussed the diet plan for the patients and how diet plans can affect the
immune responses during the disease.

1. Introduction
Leprosy is a chronic debilitating bacterial disease caused by in-
tracellular slow-growing gram-positive acid-fast bacillus Mycobacterium
leprae (M. leprae), or rarely with M. lepromatosis, identified by Gerhard
Henrik Armauer Hansen in 1873. The oldest evidence for leprosy dates
back to 600 BCE in India, while genomic studies from skeletal remains
suggest that lepromatous leprosy was present in India around 2000 B.C.
Further, the presence of leprosy during the post-urban phase of the
Indus civilization suggests that M. leprae evolved in Africa and migrated
to India before the Late Holocene, during the third millennium B.C. The
incubation period of M. leprae varies from 3 to 5 years and is spread via
air droplets of the nasal and oral discharge from non-treated multi-
bacillary leprosy patients [1] and or via digital impregnation of skin.
Interestingly over 99% of the population has adequate natural im-
munity against leprosy and 85% of the clinical cases are non-infectious.
Moreover, an infectious person can become non-infectious within a
week of the first dose of treatment [2].
Leprosy mainly affects the skin and peripheral nerves, along with
the mucosa of the upper respiratory tract and the eyes, leading to the
progressive and permanent nerve damage to deformities to paralysis.
Based on bacillary load leprosy is classified as paucibacillary (PB) and
multibacillary (MB) forms. PB leprosy is a mild form with 2–5 pale or
reddish skin lesions, whereas MB consists of more than five skin lesions,
nodules, plaques, thickened dermis or skin infiltration [2,3]. Histori-
cally, leprosy was ostracized by society for its incurable nature. Due to
the absence of any cell or animal model, understanding about the
biology of leprosy bacillus largely remains unknown. Although M. le-
prae grow in mice footpads but failed to cause nerve damage; while it
causes nerve damage in armadillos, a rarely used animal model in re-
search. The scenario has changed with the introduction of dapsone in
the 1940s and subsequently the multi-drug therapy (MDT) by the WHO
using a combination of dapsone, rifampin and clofazimine or clari-
thromycin. The MDT treatment for PB and MB varies from 6 to 12
months respectively, without relapses or recurrences or the develop-
ment of resistance, with an aim to reduce the grade two physical

∗
Corresponding author. ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi, 590010, India.
∗∗
Corresponding author. Immunobiology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
E-mail addresses: vedprakashbt@gmail.com, ved@icgeb.res.in (V.P. Dwivedi), debprasadc@yahoo.co.in (D. Chattopadhyay).

https://doi.org/10.1016/j.micpath.2019.103714
Received 25 February 2019; Received in revised form 9 August 2019; Accepted 2 September 2019
Available online 04 September 2019
0882-4010/ © 2019 Elsevier Ltd. All rights reserved.
V.P. Dwivedi, et al.
disabilities [5]. Recent studies by WHO estimated that the global
burden of leprosy was dramatically decreased from 5.2 million in 1985
to 176,176 in 2015.
Being a poor man's disease, leprosy remains a public health problem
in underdeveloped nations. The relation between the risk factors and
development of leprosy is still unclear because it is difficult to in-
vestigate the causal relationships of infection and the onset of symp-
toms due to the long incubation period (3–5 years) of M. leprae [6].
Moreover, based on the [7] classification there are five clinical forms:
tuberculoid, lepromatous, borderline tuberculoid, mid-borderline, and
lepromatous borderline. The specific risk factors for contacting leprosy,
except in endemic areas, include index patient, age of the contact,
physical distance to the patient [8] and poverty. Although its associa-
tion with susceptibility and clinical progress is unclear, many poor
countries have low prevalence rates; while economically developing
Brazil had one of the highest new case detection rate [5]. Case-control
studies on socioeconomic factors from Brazil [9] and Bangladesh [10]
revealed that food shortage at any time of life was associated with le-
prosy. It was evident that when rice prices are high and income is low,
the family is forced to reduce the number of meals a day, or the intake
of food [11]. Inadequate food intake leads to reduced intake of carbo-
hydrates, proteins, fats, vitamins, and minerals; and the nutritional
deficiency impairs the immune system against infections [12]. Al-
though the risk of subclinical infection is not always related to food
shortage, it helps in progressing the infection to the clinical disease.
Another case-control study in Indonesia [3] and Bangladesh [11] also
showed that the differences in dietary intake between new patients and
control subjects are immunity related. Despite the use of chemopro-
phylaxis and MDT, leprosy incidence is relatively stable indicating the
necessity of dietary diversity in high-prevalence areas [3]. Almost 2.5
lakh new leprosy cases are detected each year, and 7% of these cases
are grade-2 disabilities [5]. A recent review of 39 selected studies be-
tween 2006 and 2016, from Brazil, India, and Bangladesh revealed that
age, poor sanitation, socioeconomic conditions, past food shortage,
food-insecurity, household contact, manual labor, crowded household,
inequality, poor health care, and low education are the risk markers for
leprosy [13]. However, the welfare and primary health care policies on
poverty-related leprosy reduction are less known. While a close re-
lationship between social policies and health conditions of the people in
developing nations on a new case detection rate is evident from Brazil,
using national databases of 1358 municipalities during 2004–2011,
Brazilian conditional cash transfer (Bolsa Família Program) and Pri-
mary Health Care (Family Health Program) revealed that the new case
detection rate was significantly reduced in municipalities having in-
termediate, high and BFP coverage. Thus, the primary health care was
effective to record increased new case detection rate as impact of
conditional cash transfer; while the reduction of the new case detection
is due to the reduced disease incidence [14]. These findings indicated a
logical relationship between leprosy and socioeconomic factors, sug-
gesting that leprosy control policies must be targeted to the vulnerable
groups. However, the underlying mechanism between food, poverty,
and leprosy is still unclear.
2. Classification and diagnosis
Based on immune response and pathology, leprosy has been clas-
sified into five types [15]: Tuberculoid (TT), Borderline-Tuberculoid
(BT), Mid-borderline (BB), Borderline-Lepromatous (BL), and Lepro-
matous (LL). Patient with one skin lesion is categorized as single lesion
paucibacillary (SLPB), having five or fewer skin lesions without bacilli
in smears; while more than six lesions with bacilli in skin smear re-
present multibacillary (MB) form. Furthermore, TT leprosy is char-
acterized by the presence of few bacilli, a minor loss of nerve with
strong cell-mediated (IFN-γ, IL-2) and weak humoral immunity; while
LL leprosy exhibited a wide range of lesions containing multiple bac-
teria with skin and nerve involvement and strong cell-mediated
2
Microbial Pathogenesis 137 (2019) 103714
immunity (IFN-β, IL-4, IL-10). TT leprosy has a hypopigmented center
with raised erythematosus border; LL has macules, papules, and plaques
with firm nodules; while Borderline (BT, BB, BL) forms have hypopig-
mented macules. Molecular diagnosis of leprosy is usually done by 16S
ribosomal RNA gene polymerase chain reaction (PCR) assay, as most
skin lesions have no identifiable bacteria [16].
3. How leprosy cause nerve damage
One of the uniqueness of leprosy is axon demyelination that leads to
peripheral neuropathy. The nerve damage in leprosy is caused by M.
leprae after entering into the myelin sheath producing Schwann cells.
However, a recent study demonstrated that nerve damage is not directly
caused by M. leprae but through bacteria-specific phenolic glycolipid-1
(PGL-1) with myelinating glia. The M. leprae-induced nerve damage
was demonstrated in Zebrafish larvae where axonal demyelination is
initiated by the bacteria-infected macrophages, and demyelination oc-
curs in areas of intimate contact. Infected macrophages expressing PGL-
1 damage axons by producing neurotoxic response to nerve cells.
Moreover, within infected macrophages, PGL-1 induces nitric oxide
synthase that generates more reactive nitrogen species, and damages
axons by injuring mitochondria and inducing demyelination. Thus, M.
leprae can hijack the important repair mechanism and excrete toxic
chemicals to stop damage repairing process. Hence, leprosy is placed in
the same category of multiple sclerosis and Guillain-Barré syndrome
where the immune system can damage the myelin sheath [17].
4. Genetic susceptibility and metabolomic in leprosy
Genetics is an important factor for leprosy susceptibility. Exploring
the mechanism of host genetic susceptibility and clinical manifestations
observational studies from Bangladesh and Indonesia showed that ge-
netic relationship as a risk factor for leprosy among household contacts
[8,18] along with other factors [4,19,20]. Research on the relationship
of human genetics, the M. leprae genome, and leprosy susceptibility is
useful for developing a better understanding of the disease [21,22].
Detail interplays of genetics and leprosy susceptibility was outlined in a
recent review [23]. It is known that PARK2/PACRG and NRAMP1 genes
on chromosome 6q25-q27 and 2q35 are associated with leprosy sus-
ceptibility [24]. While increasing numbers of reports showed that the
innate immune response has a key role in determining susceptibility to
leprosy and its reactions with genetic regulation of the innate im-
munity, presented by polymorphisms of the NOD2 gene, that linked
with the increased susceptibility and development of leprosy reactions
[23,25]. The genetic variability is also associated with Toll-like re-
ceptors (TLRs), particularly polymorphism in TLR-1 (T1805G variant)
that impairs intracellular signaling of mycobacteria and provides pro-
tection against type 1 reactions. Genomic studies have confirmed a
correlation among individual genetics and immunity with leprosy sus-
ceptibility, as evident from the large-scale genome-wide association
study on 706 patients and 1225 controls in China. The study identified
six genes (CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, RIPK2) that
are involved in innate immune response associated with leprosy sus-
ceptibility; while variants of NOD2-mediated signaling pathway are
associated with M. leprae infection [25]. In lepromatous leprosy the
expression of galectin-3 is associated with the differentiation of
monocytes into macrophages; while the NOD2 expression is related to
the tuberculoid form by promoting monocyte differentiation into den-
dritic cells. A recent report showed that three functional components of
the inflammatory response, associated with type 1 reactions, are
regulated by a 44-gene set: (i) anti-inflammatory, (ii) proinflammatory,
and (iii) arachidonic acid metabolism mediator regulators. People with
type 1 reactions had a defective regulation of inflammatory response
against M. leprae antigens, involving anti-inflammatory and proin-
flammatory components of the innate response. These findings can help
to understand the pathogenesis and development of early diagnostic
V.P. Dwivedi, et al.
markers to identify and predict the high-risk individual of leprosy re-
actions [25].
Although the exact mechanisms of disease susceptibility, onset, and
progression of leprosy are still unclear, recent research focused on nu-
tritional, genetic and metabolic aspects of the disease, particularly fatty
acids, essential amino acids, glycoproteins, and nitric oxide synthetase.
Lipid metabolism is one of the major aspects of leprosy, as it helps to
distinguish the clinical forms. Fatty acids with anti-inflammatory and
proinflammatory role can serve as potential markers for susceptibility
and pathogenesis, as LL patients contain higher levels of omega-6 [26].
The patients having omega-3 metabolites in serum and skin after
multidrug therapy showed anti-inflammatory and pro-resolving roles,
suggesting that the host tolerance to M. leprae is a strategy to avoid
tissue damage [27]. Similarly, the tryptophan metabolizing enzyme
indoleamine 2,3-dioxygenase is responsible for immunosuppressed
status of LL leprosy in a pathogen-specific manner and can serve as a
marker for diagnosis and prognosis [28]. Analysis of serum proteome of
leprosy patients showed that differential expression of acute-phase
protein alpha-1-acid glycoprotein (AGP) isoforms and its changes in
serum level can act as putative biomarker for the diagnosis and mon-
itoring of ENL reactions [28]. In leprosy, the NO generation via nitric
oxide synthases (NOS) are regulated by IFN-γ, and the expression of
inducible i-NOS, endothelial e-NOS, and neuronal n-NOS suggest that i-
NOS expression can serve as a diagnostic marker for disease spectrum
[29].
5. Relationship of immunity and immune response in leprosy
Inter-individual variability in clinical presentation and cellular im-
mune response in leprosy acts as a model of immunoregulatory disease
in humans [30–32]. About 95% of people exposed to Mycobacterium
develop natural resistance with higher innate and cellular immunity
against M. leprae [33] and do not develop leprosy due to the low pro-
liferation rate and pathogenicity of the bacilli. Additionally, clinical
manifestation showed diverse immunological spectrum, as TT patients
showed high cellular responses to M. leprae antigens, but low antibody
titer that develops localized granulomatous disease with few bacilli. On
the other hand, the LL patients do not elicit M. leprae specific Th1 re-
sponses, but high IgM titers [34]; while borderlines are im-
munologically unstable and prone to Type 1/reversal reactions (RR)
and Type 2/erythema nodosum leprosum (ENL) [35]. Thus, an im-
balance between cellular and humoral immune response is responsible
for the different clinical form of leprosy and varied immune responses
exhibit a variety of clinical features from TT to LL. Cell-mediated im-
munity is the major defense against M. leprae (Fig. 1), and its outcome
depends on host response [36].
The intracellular life cycle of M. leprae initiates with the host cell
entry. The PGL-1 epitope on the bacterial cell wall is recognised by
complement receptor (CR)-1,3,4 mediate phagocytosis [37], and the
bacterium was recognised via molecular pattern recognition with the
help of the complement and TLRs, expressed on dendritic cells (DCs)
and macrophages [38]. M. leprae invade and survive within macro-
phages, DC and Schwann cells. The stages of M. leprae infection are
presented in Fig. 2.
After recognition by TLRs, the NF-kB is activated to release several
pro-inflammatory chemokines and cytokines like GM-CSF, TNF-α, IL-
10, IL-1β, IL-12 that activate the migration of macrophages to the
lymphoid organs to present M. leprae antigen to naïve T-cells (Fig. 3).
Cell-mediated immunity is elicited by T helper type-1 (Th-1) cells
with the secretion of IL-2 and IFN-γ; whereas Th-2 increases the hu-
moral immune response by secreting IL-4, IL-5, and IL-10. Based on
inhibitory/stimulatory signals, T-cell subsets CD4+ Th1 or Th2,
Cytotoxic T cell lymphocytes (CTL) or Th17 activate the regulatory T-
cells (Treg), which generate M. leprae-specific response in LL (Fig. 4)
patients [39,40].
Hooij A and Geluk A., 2016. Immunodiagnostics for Leprosy. In:
3
Microbial Pathogenesis 137 (2019) 103714
International text book of Leprosy. Scollard DM, Gillis TP (Ed),
American Leprosy Missions. www.internationaltextbookofleprosy.org.
It is known that IL-2 and IFN-γ are dominant in TT, whereas IL-4, IL-
5, and IL-I0 in LL [41]. Thus, the mutual relationship between cell-
mediated immunity, antibody production and resistance or suscept-
ibility to M. leprae depends on the differences in cytokine production by
T-cells. T cell activation is regulated by CD1-mediated antigen pre-
sentation pathway via major histocompatibility complex [42], influ-
enced by the nutritional status of the individual.
Host resistance against leprosy requires Th1-based responses, in-
itiated by CD4+ Th1 cells with the secretion of pro-inflammatory cy-
tokines [34] IFN-γ and TNF-α, which synergistically activate micro-
bicidal mechanisms of macrophages. Predominantly LL patients secrete
IL-10 and Th-2 producing cytokines IL-4, IL-5 and IL-13, leading to
antibody production with host defense dysregulation [43]. On the other
hand, TT leprosy is characterized by the high level of Th-1 specific pro-
inflammatory cytokines IFN-γ, IL-15, IL-1β; Th-17 differentiating cy-
tokines IL-6, TGF-β and IL-23 [44] like tuberculosis [45,46]. Thus, the
outcome of the host response to M. leprae is mainly determined by
cytokines and chemokines, which can serve as a tool to predict the
protection or progression of leprosy [47].
6. Nutrition and leprosy
The science that interprets the interaction of nutrients in food in
relation to growth, reproduction, and maintenance of health with pre-
vention or counter diseases of an organism is termed as nutrition.
Nutrition includes the intake of food, its absorption, assimilation, bio-
synthesis, catabolism, and excretion. The exact role of nutrition on
susceptibility and development of clinical leprosy is not yet established
[48,49]. Recent reports on the role of micronutrients and the immune
response in leprosy indicate a huge knowledge gap. Moreover, earlier
studies are based on either blood analyses, or on diets of cured patients.
Thus, it is difficult to determine whether leprosy is a cause or a con-
sequence of nutritional deficiencies [50–53]. As M. leprae is an in-
tracellular bacterium, so host defense is based on cell-mediated im-
munity (Figs. 1 and 3). Previously it has been reported that protein
deficiency along with inadequate or low intake of vitamins and mi-
nerals rich food from diverse food groups is linked to a reduced cell-
mediated immunity [54], which put leprosy patient at risk of reduced
immunity. Moreover, the phenomenon of “immune reconstitution”
found in HIV cases after anti-retroviral therapy may have a role in le-
prosy [55,56]. Immunosuppressed HIV patients suffer prolonged nu-
tritional deficiencies, and if such patients are supplied with good food
the body responds to infection by developing clinical disease. Com-
pared to the normal population leprosy patients are financially poor
and unable to spend on food, have less household food stocks and di-
verse diet. Thus, the patient had low consumption of proteins (such as
eggs, fish, meat, and milk), vitamin and mineral rich fruits and vege-
tables. It was observed that leprosy patients have less access to socio-
economic, health and nutritional factors compared to the control po-
pulation [11]. The main factors for increased risk of leprosy include
lower income, food expenditure, BMI, and dietary diversity score (DDS)
with an absence of household food stocks and past year food shortage
[11]. Collectively, the infection course depends on host genetic factors
and is influenced by environmental and nutritional status [24,57,58].
Nutritional deficiencies are common in leprosy endemic areas, so that
there is a possibility that the clinical presentation is a result of nutri-
tional deficiencies along with environmental and genetic factors of the
host. Nutrition and food supplements are known to influence the im-
mune response in many diseases. A deficiency of vitamins and trace
elements affect the innate and adaptive immune response [12].
7. Immune response and influence of nutrition in leprosy
The human body with uniform temperature provides a nutrition
V.P. Dwivedi, et al. Microbial Pathogenesis 137 (2019) 103714

Fig. 1. Immune responses in active leprosy [36]. Th1–Th2 paradigm: insights from leprosy. J Invest Dermatol 102: 828–832.

rich environment and serves as an attractive host for pathogens.
However, its natural barriers (mechanical, chemical, biological) and
immune response protects the body from pathogens. The skin, epithelial
and mucosal (respiratory and digestive mucosa) surfaces, with ciliary
and peristaltic movement constitute its mechanical barrier; while fatty
acids, bactericidal lysozyme (saliva, sweat, tears), proteolytic enzymes
(stomach and intestines), stomach acid and anti-bacterial peptides of
skin and intestine provide the chemical barrier. The microbiome (in-
testinal flora) and epithelium receptors compete with pathogens for
nutrients and produce microbicidal substances [59]. Once a pathogen
overcomes these barriers, host immune response gets activated, and the
control of infection depends on the ability of hosts to produce a counter-
response against the invading pathogen [60]. Nutritional deficiency not
only causes the suppression of immune responses, but several micro-
nutrients help to maintain the integrity of natural barriers, and the
function of the immune system [61]. Clinical manifestations of infec-
tion can also occur due to tissue inflammation mediated by the immune
response, as TNF-α, NO and reactive oxygen species (ROS) having mi-
crobicidal action can induce tissue damage. Thus, antioxidant sub-
stances (endogenous or nutritional) and cytokine modulations are es-
sential for a balanced immune response for host protection and
pathogen control [62]. The effect of malnutrition are variable and
difficult to measure during infection; while a nutritional deficiency may
increase the susceptibility and aggravate the disease prognosis in TB
and measles [63]. Moreover, persistent pathogens can cause auto-
immune and inflammatory diseases, while most pathogens trigger an

Fig. 2. Different stages of Leprosy Infection. Treatment of Leprosy in the early 21st century. Dermatologic Therapy 22(6): 518–537.

4
V.P. Dwivedi, et al.
Fig. 3. Innate and acquired immunity to Mycobacterium leprae infection [28]. Advances in leprosy immunology and the field application: A gap to bridge. Clinics
in Dermatology 34(1): 82–95.
Fig. 4. Schematic representation of T cells involved in leprosy disease
spectrum.
inflammatory response. Thus, nutritional factors have a role to de-
termine the outcome of the diseases [64].
The risk of contracting leprosy is reported to be associated with
poverty, dietetic inadequacy, reduced intake of calorie, proteins,
5
Microbial Pathogenesis 137 (2019) 103714
vegetables, and fruits [9]. Studies from India and Brazil demonstrated
that an imbalance of dietary intake is related to feeding habits due to
the lack of knowledge about the nutritional value of foods [50,65]. Low
body weight or overweight people also have dietetic inadequacies while
overweight persons consume empty calories. A study in Brazil revealed
that 41.9% of leprosy patients are overweight to obese while 3.6% were
underweight [65]. The low quality of diet is associated with a higher
risk of leprosy due to low intake of antioxidants that impaired immune
defense against M. leprae [1,50,66]. Another study with 58 leprosy
patients showed that nutritional deficiency in different forms of leprosy,
leads to decreased serum levels of vitamin A (retinol), C (ascorbic acid),
D (cholecalciferol), and E (tocopherol), along with magnesium, sele-
nium, and zinc [66]. During leprae infection, macrophages get acti-
vated and kill the bacterium by the generation of ROS, NO, and RNS
which are known to kill intracellular microbes. However, these radicals
have oxidant activity and thus can cause tissue damage due to high
inflammation. Dietary antioxidants can counterbalance these effects of
oxidative stress, and thus a reduction of antioxidant levels can com-
plicate the treatment and disease progress [67].
8. Vitamin A in leprosy
Vitamin A along with its precursor's retinoic acid and β-carotene are
important antioxidants that interact with peroxyl free radicals and
hydroperoxides by inhibiting lipid peroxidation [68], while carotenoids
quench the cellular singlet oxygen into less reactive species [69]. Beta-
carotene act as an antioxidant in low partial oxygen pressures, while in
high oxygen concentration vitamin E complement this action. As in-
creased oxidative stress documented in leprosy patients [1] indicate the
requirement of vitamin A. Vitamin A is also required to regulate the
immune response of innate (cellular) and acquired (humoral) immunity
V.P. Dwivedi, et al.
[70]. Thus, deficiency of vitamin A is associated with decreased pha-
gocytosis, oxidative burst of macrophages [61] and regulation of the NK
cell population [71]. Moreover, vitamin A deficiency is reported to
decrease IFN-γ production (Th1 response) and Th2 mediated humoral
responses [12,72]. An Indonesian study showed that vitamin A defi-
cient children produce fewer IFN-γ and become susceptible to myco-
bacterial diseases as IFN-γ producing Th1 cells provide protection
against intracellular pathogens [12]. Furthermore, retinoic acid in-
duced IL-10 production as an anti-inflammatory response by inhibiting
IL-12 and TNF-α. As IL-12 helps to induce Th1 differentiation, thus the
supply of vitamin A inhibits Th1 response, indicating that vitamin A
deficiency compromises Th2 responses and decreases IgG1 and IgE
antibody production [12,72]. The decrease in serum concentrations of
vitamin A in LL patients can reduce Th1 response and M. leprae re-
plication in macrophages [1]. Another example is the induction of Treg
cells by Schistosoma mansoni egg (antigen w1) depend on vitamin A that
down-regulate Th1 and Th2 responses to control inflammatory and
autoimmune diseases.
9. Vitamin C in leprosy
Vitamin C (ascorbic acid) is an enzymatic co-factor in many meta-
bolic processes, especially in oxidation-reduction processes; thus es-
sential for the prevention of infections, and its deficiency affects the
immune response [74]. Vitamin C also helps in the absorption of iron
and inactivation of free radicals [75]. As a non-enzymatic antioxidant,
vitamin C helps to control ROS-induced inflammation while killing
intracellular bacteria like M. leprae; along with the damage of the im-
mune system through oxidative attacks. ROS-induced oxidative stress
can also damage the cell membrane integrity, with alteration in mem-
brane permeability and cell-to-cell communication, which also affects
the host immune responses [62,76]. Supplementation of vitamin C
(20 mg/kg and 1–3g per day) in the food can enhance the activity of
neutrophils and macrophages to kill the microbes. It has been reported
that vitamin C treatment enhances the phagocytotic activity of murine
macrophages [74]. Thus, deficiency of vitamin C adversely affects le-
prosy patients, as evident from the reduced serum level of ascorbic acid
in TB patients [77,78]. Moreover, supplementation of vitamin C
(1.0 gm ascorbate) and vitamin E (600 mg) improved the plasma anti-
oxidant capacity of pulmonary TB patients after a month of MDT [79].
10. Vitamin D in leprosy
Mycobacterium leprae and M. tb are intracellular bacteria with si-
milar host defense, and recent studies showed that vitamin D deficiency
leads to an increased incidence of TB [70,80]. For long, vitamin D was
considered to be essential for mineralization of bones, but after the
discovery of functional vitamin D receptors (VDR) in tissues that are not
involved in calcium and phosphate metabolism, another role of vitamin
D has been accepted. The VDRs, present in many tissues and cells, elicit
a variety of biological responses including immunomodulatory activity
by modulating antigen presenting cells and T cell function [75,81].
Serum samples from TB susceptible individuals showed a low level of
25-hydroxyvitamin D and less efficiency to cathelicidin peptide [82].
Moreover, vitamin D can induce the production of antimicrobial pep-
tides in infected macrophages that kill Mycobacterium (Fig. 5). These
peptides (cathelicidins and defensins) modulate innate immune re-
sponse [83]. The cathelicidin peptide LL-3 recruits monocytes, T-cells
and neutrophils to the infection site; while LL-37 activates macrophages
by binding to TLR to induce M.tb killing. A comparative study on ca-
thelicidin and vitamin D3 in 29 leprosy patients with 19 healthy in-
dividuals showed that cathelicidin level is lower in leprosy patients
than healthy individuals [84]. The IFN-γ, secreted by Th1 cells is known
to have a protective role against intracellular pathogens, and can po-
tentiate the effect of 1α-hydroxylase enzyme that converts vitamin D
into its active form 1α, 25-(OH)2D3, along with the inhibition of an
6
Microbial Pathogenesis 137 (2019) 103714
enzyme that inactivate vitamin D3 [85]. On the other hand, vitamin D3
helps to disseminate M. leprae by inducing dendritic and T-regulatory
cells by inhibiting co-stimulatory molecules and inducing FOXp3 ex-
pressions and IL-10 production [86]. Infectious diseases are multi-
factorial but influenced by environmental and genetic factors. A poly-
morphism in the vitamin D receptor gene (codon 352 C/T) can regulate
the active metabolite of D3 and affect bone mineralization as well as
Th1/Th2 immune response. Individuals with ‘tt’ homozygous alleles
develop Th1 response, while the ‘TT’ homozygous alleles develop Th2
response. In a case-control study it was shown that genotype ‘tt’ was
less frequent in TB patients, while another study with 231 leprosy pa-
tients (107 TT and 124 LL) showed that genotype ‘tt’ was associated
with polymorphism in vitamin D receptor gene (codon 352 C/T) in
tuberculoid leprosy, but genotype ‘TT’ was associated with LLs leprosy
while the resistance in developing leprosy is due to the heterozygous
genotype ‘Tt’. These data suggest that VDR and vitamin D play an im-
portant role in TB and leprosy. Therefore, the evaluation of vitamin D
deficiency and polymorphism of its receptor can help to predict the
clinical evolution and its dietary role in leprosy. TT patients trigger a
protective vitamin D-mediated antimycobacterial innate immune re-
sponse by the production of cathelicidin and defensin beta (DEFB)-4
[33]. Conversely, an LL patient lacks activation of the vitamin D-
mediated pathway and reduced expression of defensins. Thus, further
investigation is required to determine whether any of these mediators
can act as biomarkers in leprosy diagnosis.
11. Vitamin E in leprosy
Free radicals and lipid peroxidation lead to the suppression of im-
mune response. Vitamin E, a fat-soluble antioxidant, protects the lipid
membranes against peroxidation. In influenza-infected rats, vitamin E
rich diet showed increased production of IL-2 and IFN-γ suggesting that
higher intake of vitamin E improves the immune response against in-
fections [87]. Vitamin E in its most active form α ± -tocopherol, react
with phospholipids of mitochondria, plasma membrane and endoplas-
matic reticulum as the first defense against peroxidation of membrane
phospholipids. The tocopherols help to neutralize these reactions by
donating phenol hydrogen to the peroxyl free radical (Fig. 6).
This inhibition of lipid peroxidation by vitamin E usually aided by
vitamin C to reduced glutathione and NADPH, as the higher con-
centration of vitamin E has a pro-oxidant effect. A case-control study of
leprosy patients, at the beginning of treatment, showed increased oxi-
dative stress with higher levels of lipid peroxidation due to free radicals
formed during the immune-mediated killing of M. leprae. However,
leprosy patients treated with MDT (dapsone, rifampicin, and clofazi-
mine) and 400 IU of E daily for 12 months showed normal LPO levels
[88] similar to TB [89,90]. Compared to healthy controls TB patients
showed reduced level of vitamin C and E, but higher serum level of
Malondialdehyde [90], while pulmonary TB patients receiving standard
chemotherapy when supplemented with 140 mg of E and 200 μg of
selenium for two months showed reduced oxidative stress with im-
proved antioxidant status than TB patients treated only with che-
motherapy [89].
12. Role of zinc in leprosy
Zinc is known to help in the prevention of infections, and its defi-
ciencies can negatively affect the immune system [74] due to poor Th1
response with a reduced level of pro-inflammatory cytokines (IFN-γ, IL-
2, and TNF-α) that help to control intracellular pathogens including M.
leprae, without affecting the level of IL-4, IL-6, and IL-10 [91]. While
prolonged zinc supplementation increased the production of IL-2
leading to significantly decreased incidence of respiratory infections
[91]. The antioxidant role of zinc is associated with the regulation of
cysteine-rich low molecular weight protein metallothionein expression
during radiation, drugs and heavy metal exposures [92]. Moreover, zinc
V.P. Dwivedi, et al.
Fig. 5. Roles of Vitamin D during Mycobacterium leprae infection [19]. Vitamin D and tuberculosis. Nutr Rev. 67: 289-293.
is a structural and catalytic component of superoxide dismutase (SOD),
which reduces the oxidative effect of ROS, transforming superoxide
(O2-, +O2-, +2H+) to hydrogen peroxide (H2O2 + O2) to minimize
the chain reaction during cellular injury. The cytoplasmic SOD contains
copper-zinc, while mitochondrial forms have manganese [93]. Thus,
the loss of zinc in the cellular membrane can affect its function, flow,
hydro-osmotic balance and sodium-calcium transport channels of the
cell. Further, zinc can stabilize the reduced form of sulfhydryl groups,
and protect cell membranes from the effects of lipid peroxidation [94].
A study showed that Zn deficiency in HIV infected males may con-
tribute to secondary infections that can lead to increased morbidity and
mortality [95].
13. Selenium and immune response
Essential micronutrient trace element selenium is strongly linked
with complex enzymatic and metabolic functions in the living system,
and the most important is its interaction with glutathione peroxides
(GPxs). Glutathione catalyzes the reduction of hydrogen peroxide and
organic hydroperoxides and also protects cell membrane and cellular
lipids from oxidative injuries [96]. Selenium affects the chemotactic
and microbicidal activities of innate immune components and mod-
ulates leukotriene synthesis and peroxide regulation in immune cells
[96,97]. However, an optimal dose of selenium is required for phago-
cytosis and lymphocytic activity, but higher doses are inhibitory.
Clinical studies showed that TB, asthma, and HIV patients have a se-
lenium deficiency, but its effects on leprosy infection are unknown
[98,99]. It has been observed that high doses of any single antioxidant
might induce an opposite effect. Thus, it is very important to consider
the biochemical, clinical and genetic aspects during the
7
Microbial Pathogenesis 137 (2019) 103714
recommendation of nutrients, and their doses for the prevention and
treatment of diseases.
14. Food and leprosy management
Food and its availability is a significant factor for leprosy prevention
and management. The majority of leprosy patients are from low socio-
economic strata, having acute to chronic lifelong food insecurity,
having economic, social to physical dimensions. Even if leprosy patients
have economic access to food they may not have physical and social
access to quality and quantity of food during treatment [5]. Although
Government provides food grains for families living below the poverty
line (BPL), leprosy patient must have their own resources for nutritional
security. As leprosy patients are usually nutrient deficient, so a further
nutritional deficiency can impair their cellular immunity to poor de-
fense against infections. Moreover, the risk of contracting subclinical M.
leprae infection could facilitate the progression from infection to clinical
manifestation. Therefore, in order to make MDT successful, it is a must
to promote low-cost high protein balanced diet among leprosy patients
receiving MDT, and important to make them understand that MDT
along with locally available high protein diet is essential for leprosy
cure. Here we have provided general dietary guidelines for boosting
immunity including the diverse food groups and types for people with
or contracting leprosy to keep their immune system function with a
low-cost diet chart for sufferers and their household (Table 1).
To recommend a specific diet plan for leprosy patients, we have
considered their socio-economic condition, day-to-day physical activ-
ities, and food preferences. The guidelines will be more useful if foods
are consumed in natural form. (i) Sprouted pulses: It is better to con-
sume germinated or sprouted pulses instead of cooking dry pulses,
V.P. Dwivedi, et al. Microbial Pathogenesis 137 (2019) 103714

Fig. 6. Role of ROS and Vitamin E during Mycobacterium leprae infection. Vijayaraghavan R, Suribabu CS, Sekar B, Oommen PK, Kavithalakshmi SN,
Madhusudhanan N (2005). Protective role of vitamin E on the oxidative stress in Hansen's disease (Leprosy) patients. Eur J Clin Nutr 59(10): 1121–1128.

Table 1
Food groups and types with a low-cost Diet Chart for Leprosy (Approximately 2000 Calorie; Protein: 60 gm; Fat: 25 gm).
Food Group Quantity (gm) Types of food

Cereal 370–400 Brown rice, wheat, Ragi, Jawar, Bajra

Pulses 50 Mixed pulses, whole pulses,
Vegetables 350 Locally grown: Green leafy vegetables, Tomatoes, Brinjal, Bitter gourt, Pumpkin etc.
Roots-tubers 100 Carrot, Onion, Potatoes, Sweet potato, Tapioca, Yam
Oil 20 Cooking with Mustard, Sesame or Ground nut oil
Diary/meat/Fish 50 Egg or small Fishes for non vegetarian patients
Molasses 20 Instead of sugar
Nuts 15 Ground Nut or other locally available Nuts
Fruits 150 Amla, Guava, Lemon, Banana, Jamun, Berries, Mango and other locally grown fruits

No. Meal Plan Benefits

1 Early Morning Luke warm water (200 ml) + Curcumin + Black Pepper Curcumin and pepper have unique health benefits. Black pepper in combination
with turmeric enhanced the antiseptic and antibacterial properties of turmeric
with ideal wound healing and cleansing activities. Pepper increases the wound
healing ability of turmeric due to better absorption at small doses (¼ to half tsp
and gradually increases to one tsp three times daily).
2 Breakfast (After half Missi Roti (3 Pcs)/Chira (60 gm)/Mixed Veg (1 Bowl Nutrient dense Breakfast (30% of daily requirement). Need attractive, healthy and
an hour) −100 gm) + Dahi (100 gm) + one Boiled Egg tasty meal with Protein, Vitamin and Mineral from different food groups.
3 Mid-Morning Fruits (seasonal −150 gm) Micronutrients work with macronutrients to keep the body functioning and
maintain energy level, metabolisms, cellular function, physical and mental
wellbeing.
4 Lunch Rice (150 gm), Dal (25 gm), G.L.V (50 gm); Veg (200 gm), Soya/ Healthy nutrient packed lunch helps organs and tissue to work effectively.
Paneer (40 gm) or Fish/Chicken (65 gm) Without good nutrition body is more prone to disease, infection, fatigue and poor
performance.
5 Afternoon Pumpkin seed/Mixed seeds (15 gm) Pumpkin seeds are rich in antioxidant, iron, zinc, magnesium, carotenoids,
vitamin E that help to protect against disease and inflammation. Nuts are high in
healthy fats, protein and fibre.
6 Evening Badam/Chhola/Chhatu (25 gm) Snacking help to fit extra nutrients into diet and prevent overeating at meal times.
7 Dinner Wheat/Rice (100 gm) Need enough food from different food types. Meal with a variety of food types
Dal (25 gm); Veg (100 gm) helps to satisfy satiety and supply nutritious.

**Drinking Water: 2–2.5 L (10–12 glasses).

8
V.P. Dwivedi, et al.
because sprouted pulse contains diverse micronutrients (copper, iron,
magnesium, phosphorus, potassium), vitamins (Thiamine or B1,
Riboflavin or B2, Niacin or B3, Pyridoxine or B6, Folic acid), protein,
carbohydrate (low level) and fibers. One bowl of sprouted moong dal
(Vigna radiata) contains 1 g fat and only 30 Calories with overall health
benefits. (ii) Yogurt: a fermented food helps in digestion and improves
pH balance in intestine to provide better digestive health. The
Lactobacillus sp helps in forming omega 3 fatty acids, essential for
strengthening the immune system. (iii) Poppy and sesame seed:
Consumption of poppy seeds is a traditional food practice in India, to
get good quality and quantity of protein. Both of these seeds are rich in
the essential minerals magnesium and calcium; help in converting LDL-
cholesterol to healthy HDL-cholesterol (iv) Zinc: Zinc has been used
since ancient Egyptian times to enhance wound healing. Leprosy pa-
tients may be benefited from food rich in zinc. Normally meat, fish, egg,
nuts, legumes and whole grains are good sources of zinc. Thus, these
foods are helpful for leprosy patients to heal their ulcers faster.
Although zinc is considered safe at the recommended dosages, more
studies are required for a definitive conclusion [100]. (v) Omega-3 fatty
acid: It is a highly nutritious vital food that provides an essential
polyunsaturated fatty acid. Sea fish, flax seeds, soya bean, peanut, and
other nuts produce omega 3. Fish oil contains both forms of Omega 3:
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Omega-
3 fatty acid may help to treat leprosy symptoms but well-designed
studies with clear evidence are lacking. An omega-3 fatty acid is con-
sidered safe if taken in doses of recommended dietary allowance (RDA)
that also helps in blood clotting, making cell membranes, and prevent
inflammation [101]. Omega-3 and omega 6 mediators are found to be
involved in the regulation of M. leprae-specific inflammatory and im-
mune responses, as these mediators are present in different forms of
leprosy-before and after MDT and during T1R as described in a recent
review comparing the role of lipid mediators in leprosy including cy-
steinyl leukotrienes, leukotriene B4, prostaglandin E2 and D2, lipoxin
A4 and resolvin D1 on erythema nodosum leprosum [101].
15. Discussion and conclusion
Leprosy displays a variety of clinical features with complex pre-
sentation and multifactorial risk, thus its management is a huge chal-
lenge. The majority of individuals is neither infected nor develops le-
prosy following regular exposure due to their natural immunity. Even
people with latent M. leprae infection may develop only a single self-
healing lesion, but if untreated or unhealed it may progress into the PB
or MB [102]. Recent studies showed that NOD2-mediated signaling
[103], vitamin D-dependent antimicrobial pathways [104], interferons
[105], T-regulatory Th-17/IL-17A/IL-17F cytokines, CD163 and ga-
lectin-3 [106] have role in leprosy control. However, the intracellular
bacterium M. leprae could avoid immune surveillance, despite the in-
nate immune response by the skin epithelium and keratinocytes during
bacterial entry into the skin and peripheral nerves, while keratinocyte
elicits an immune response by mannose-binding receptors, TLRs, cy-
tokines, chemokines and antimicrobial peptides [107]. Moreover,
human keratinocytes have the phagocytic ability with the expression of
antimicrobial factors CD80, CD209, cathelicidin, TNF-α and IL-1β; and
M. leprae induce cytokines and chemokines in keratinocytes to kill the
bacterium with the help of LCs, DCs, T-cells, and neutrophils [108]. So
the best way to prevent the spread of leprosy is early diagnosis and
treatment. Immediate and annual examinations are necessary for at
least five years after last contact with an infectious patient with ade-
quate nutritious diets to the victim, family members, and close contacts
to improve/strengthen immunity.
Leprosy can serve as a spectral model of innate and adaptive im-
mune response so far protection and pathogenesis are concerned but are
relatively understudied in relation to its impact on nutritional factors.
Leprosy is known to be influenced by genetic and environmental factors
and the patient's reduced antioxidant status. The importance of
9
Microbial Pathogenesis 137 (2019) 103714
nutrition, particularly the balance of protein and micronutrients need to
be investigated, as the disease takes a long time to develop, and thus the
nutritional balance may reduce the risk of acquiring the disease.
Moreover, a reduction in antioxidant and nutrient levels leads to in-
creased oxidative stress, along with skin and neurological disorders
during M. leprae infection. Thus, further studies on the role of nutrients,
particularly immuno-modulatory nutrients need to be re-investigated to
elucidate pathogenic mechanisms. Collectively, this review highlighted
the current status of leprosy and its immune mechanism with the role of
food and nutrition in its management. The supply of nutritious food to
all members of a leprosy patient household is the most important factor
along with related parameters including BMI, per capita food ex-
penditure, food storage, etc. Poverty alone leads to low consumption of
protein foods, fruits, and vegetables leading to nutritional deficiency,
and prolonged nutritional deficiencies lead to an impaired immune
response, leading to clinical leprosy. Thus, future research should be
directed on the association of leprosy and nutrition, and the role of the
immunoregulatory pathway for leprosy management.
Conflicts of interest
All authors have declared no conflict of interest.
Funding statement
There is no financial support for this study.
Acknowledgment
DC conceived this review and drafted the manuscript. VPD finalizes
the review with DC; BB helped in figure preparation. AS and MD help
DC in preparing the nutrition part, while AB, ID and SB help to compile
this review. All authors revised, read and approved the final review.
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