REVIEW

CURRENT
OPINION New findings in the pathogenesis of leprosy and
implications for the management of leprosy
Anastasia Polycarpou a, Stephen L. Walker a, and Diana N. Lockwood a,b

Purpose of review
This review focuses on recent work in leprosy pathogenesis. New research of both innate and adaptive
immune responses to Mycobacterium leprae is described. The proposition that Mycobacterium lepromatosis
is a new species causing leprosy is discussed.
Recent findings
Modulation of the lipid metabolism and reprogramming of adult Schwann cells have both been suggested
as mechanisms used by M. leprae to disseminate the disease. New markers associated with localized,
disseminated disease or the occurrences of leprosy reactions include the human interferons, CD163,
microRNA-21, NOD2, galectin-3 and toll-like receptor 4. The role of keratinocytes instead of macrophages
is underlined in the pathogenesis of leprosy. Adaptive immunity reports focus on the role of T regulatory
cells and cytokines secreted by T helper cells in leprosy. Finally, a newly identified species named M.
lepromatosis has been detected in patients with leprosy and severe erythema nodosum leprosum.
Summary
Novel biological pathways have been identified to be associated with the clinical phenotype of leprosy or
the occurrence of leprosy reactions. Future work should include larger numbers of clinical samples from
across the leprosy spectrum in order to give new insights in the pathogenesis and management of the
disease.
Keywords
erythema nodosum leprosum, leprosy, Mycobacterium leprae, Mycobacterium lepromatosis, type 1 reactions

INTRODUCTION erythema nodosum leprosum (ENL) is considered an

Leprosy is a chronic granulomatous disease affecting
mainly the skin and peripheral nerves, which is
caused by infection with the intracellular bacterium
Mycobacterium leprae [1]. There are still more than
200 000 new leprosy cases registered globally each
year [2]. The pathology of leprosy is determined by
the immune response to M. leprae, resulting in a
clinical range from tuberculoid through borderline
forms to lepromatous leprosy as classified by Ridley
and Jopling [3]. Multidrug therapy (MDT) compris-
ing a combination of the drugs dapsone, rifampicin
and clofazimine is successfully used in treating
the infection. Despite MDT, leprosy can be compli-
cated by acute inflammatory episodes called leprosy
reactions.
Type 1 or reversal reaction (T1R) affects skin
lesions and nerves and is considered a delayed
hypersensitivity reaction characterized by the
infiltration of skin and nerve lesions by CD4þ
lymphocytes secreting high levels of interferon
(IFN)-g and tumor necrosis factor-a [4]. Type 2 or
immune complex-mediated complication of leprosy
[5], characterized by crops of tender erythematous
nodules, systemic manifestations such as fever,
malaise and inflammation elsewhere producing iri-
tis, lymphadenitis, orchitis, arthritis and neuritis [6].
Treatment of leprosy reactions with corticosteroids
is not always effective in limiting the nerve function
impairment, which may lead to disability and
deformity [7].
This review focuses on the pathogenesis of M.
leprae infection and leprosy reactions, identification
a
Department of Clinical Research, Faculty of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine and bThe
Hospital of Tropical Diseases, London, UK
Correspondence to Anastasia Polycarpou, Department of Clinical
Research, Faculty of Infectious and Tropical Diseases, London School
of Hygiene and Tropical Medicine, Keppel street, London WC1E 7HT,
UK. Tel: +442 076 122 642; e-mail: Anastasia.Polycarpou@lshtm.ac.uk
Curr Opin Infect Dis 2013, 26:413–419
DOI:10.1097/QCO.0b013e3283638b04

0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Tropical and travel-associated diseases
KEY POINTS
 M. leprae interacts with the host cell lipid metabolism in
order to favor intracellular bacterial survival and this
can be modulated by clofazimine.
 M. leprae infection may be spread to other tissues by
reprogramming of adult Schwann cells.
 The expression of NOD2 is associated with tuberculoid
leprosy by inducing differentiation of monocytes into
dendritic cells whereas the expression of galectin-3 is
associated with lepromatous leprosy by promoting
differentiation of monocytes into macrophages.
 Keratinocytes, but not macrophages, may respond to
M. leprae by upregulating b-defensin 3, induced by
type 1 reactions and suppressed by corticosteroids.
 M. lepromatosis may be a new causative agent for
diffuse lepromatous leprosy and leprosy reactions, but
further investigation is required.
of new biomarkers for susceptibility and prognosis,
and it summarizes recent literature.
MYCOBACTERIUM LEPRAE
PATHOGENESIS
Recent studies have investigated how M. leprae influ-
ences the host cell lipid metabolism in order to favor
intracellular bacterial survival and how this can be
modulated by MDT. Moreover, a new model for
leprosy dissemination by reprogramming adult
Schwann cells has been identified.
Mycobacterium leprae and host lipid
metabolism
The histology of lepromatous leprosy lesions is
characterized by foamy macrophages due to the
accumulation of host-derived lipids [8–9]. Lipid
droplets are lipid storage organelles found in all cell
types. It has been shown that M. leprae induces lipid
droplet biogenesis in macrophages [9] and Schwann
cells [10], creating a favorable niche for its own
survival. Adipophilin/adipose differentiation-
related protein (ADRP) has an essential role in fatty
acid transport, inducing lipid accumulation [11],
and has opposing functions to hormone-sensitive
lipase (HSL), which favors lipid degradation [12].
Previous work has shown that M. leprae increases the
expression of ADRP in macrophages [13]. Recent
work by Tanigawa et al. [14] shows that the expres-
sion of HSL can be suppressed by live but not dead
M. leprae in macrophages. Protein kinase A phos-
phorylates HSL on Ser563 and 50 -AMP-activated
414 www.co-infectiousdiseases.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
protein kinase on Ser565, both serine residues
required for the function of HSL. Interestingly, it
has been described that 1 h after infection with M.
leprae, HSL expression is suppressed and there is also
decreased phosphorylation of the two serine resi-
dues [14].
The commonest laboratory test for diagnosis
and classification of leprosy patients is the slit-skin
smear in which microscopy is used to identify the
presence of acid-fast bacilli. In the study of Tanigawa
et al. [14], HSL expression was undetectable in the
slit-skin smear specimens from five lepromatous and
four of seven borderline lepromatous patients. The
result suggests that the low HSL levels in dissemi-
nated disease could provide a new molecular mech-
anism for M. leprae to preserve host lipids. Increase
of HSL occurred in slit-skin smears of two borderline
patients experiencing T1Rs and four patients after
successful treatment with MDT [14]. The same
group showed that clofazimine is the drug of
MDT causing this effect in vitro, as it attenuated
the mRNA and protein levels of ADRP, whereas
increased those of HSL in M. leprae-infected human
premonocytic THP-1 cells [15]. Clofazimine not
only antagonizes the effects of M. leprae on the
modulation of ADRP and HSL, but also leads to a
decrease of lipid droplet accumulation driven by M.
leprae infection, modulating lipid metabolism in M.
leprae-infected macrophages [15]. Rifampicin and
dapsone did not significantly affect ADRP or HSL
expression levels [15]. ADRP and HSL mRNA and
protein levels were evaluated in slit-skin smear and
skin biopsy specimens from a leprosy patient before
and after treatment, showing decrease of ADRP and
increase of HSL after MDT [15]. This study suggests a
new mechanism of action for the drug clofazimine.
A future study including more clinical samples
would be useful in order to correlate ADRP and
HSL expression with the clinical course of leprosy.
Mycobacterium leprae and reprogramming
adult cells
The neural tropism of M. leprae is due to its binding
to the G domain of the bridging molecule laminin-
a2 [16], and a-dystroglycan serves as the Schwann
cell receptor for M. leprae [17]. M. leprae induces
demyelination of myelinated Schwann cells, mak-
ing Schwann cells more prone to invasion by the
bacillus, in a Rag1
/
mouse model lacking mature B
and T lymphocytes [18]. This demyelination process
by leprosy bacilli is mediated by tyrosine kinase
signaling through the ErbB2 receptor [19]. It is
not known how colonization of Schwann cells
by M. leprae leads to the spread of infection to
other tissues. The in-vitro and murine in-vivo study
Volume 26  Number 5  October 2013
 New findings in the pathogenesis of leprosy Polycarpou et al.
&&
by Masaki et al. [20 ] investigated further the inter-
actions of M. leprae with Schwann cells and
suggested a novel model to explain the spread of
the infection. The study suggested that M. leprae
bacilli interact with and change the fate of Schwann
cells to progenitor/stem cells with mesenchymal
&&
characteristics [20 ]. The cell reprogramming fol-
lows the silencing of the master regulation of
&&
Schwann cell lineage Sox10 [20 ]. M. leprae, there-
fore, promotes dissemination of disease through
two mechanisms: direct differentiation of Schwann
cells to mesenchymal tissues and formation of gran-
uloma-like structures that release bacteria-bearing
&&
macrophages [20 ]. This study increases our under-
standing of adult tissue cell plasticity and indicates
for the first time that a bacterium may lead to
reprogramming of adult cells into stem cells. How-
ever, in order to demonstrate this effect, Schwann
cells were infected with a very high number of M.
leprae bacilli (multiplicity of infection >50) with
&&
>90% infection efficiency [20 ]. Moreover, the
methodology used nude mice that lack T cells, over-
simplifying the inflammatory microenvironment to
&&
predominantly macrophages [20 ]. Therefore,
although the study describes an attractive in-vitro
model to explain M. leprae pathogenesis, more
research is needed before conclusions can be
extrapolated to human disease.
INNATE IMMUNITY
Several recent studies compared the immune
response of borderline tuberculoid with leproma-
tous leprosy patients, to identify new biomarkers
and biological pathways associated with the clinical
phenotype of the disease. New potential biomarkers
for T1Rs have been identified, but there is still a lack
of studies on ENL.
Borderline tuberculoid vs. lepromatous
leprosy
Liu et al. [21] used microarrays to reveal increased
gene expression of 13 microRNAs in skin biopsy
specimens from five lepromatous leprosy vs. six
borderline tuberculoid untreated patients, with
microRNA-21 being the most highly expressed in
lepromatous leprosy vs. borderline tuberculoid
lesions. Real-time PCR (RT-PCR) demonstrated
the high expression of microRNA-21 in the lepro-
matous leprosy lesions, and fluorescent in-situ
hybridization revealed that the microRNA-21-
positive cells in the sections were located within
the granulomas [21]. The study also demonstrated
that microRNA-21 inhibited gene expression of
the vitamin D-dependent antimicrobial pathway
0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
by downregulating key genes in the toll-like recep-
tor (TLR)-induced antimicrobial pathway [21],
which are triggered in monocytes/macrophages
when they detect M. leprae infection [22]. This study
supports the finding that monocytes/macrophages
on detecting M. leprae trigger the vitamin D-depend-
ent antimicrobial pathway [22], but that this
response is at the same time inhibited by the upreg-
ulation of microRNA-21 by M. leprae itself [21].
Human interferons (IFN) are classified according
to the type of receptor through which they signal.
Therefore, IFN-a and IFN-b are type I IFNs, whereas
&&
IFN-g is type II IFN. A study by Teles et al. [23 ] used
microarray data analysis to associate type I and type
II IFN genes with the outcome of host response in
leprosy. The study showed that IFN-g-specific genes
were preferentially elevated in borderline tubercu-
loid lesions and T1Rs, and IFN-b and its downstream
genes, such as interleukin (IL)-10, were more
&&
detected in lepromatous leprosy lesions [23 ]. In
addition, mRNA was isolated from skin lesions of 10
lepromatous leprosy, 10 borderline tuberculoid and
10 T1Rs patients and RT-PCR was performed, which
showed higher expression of IFN-b mRNA in lep-
romatous leprosy lesions and IFN-g mRNA in bor-
derline tuberculoid and T1R lesions. Protein
expression of IFN-b was also more evident in lep-
romatous leprosy lesions and was localized in
macrophages. When IFN-g-induced genes in border-
line tuberculoid lesions were analyzed, several anti-
microbial pathways were revealed, including the
vitamin D-dependent antimicrobial pathway
&&
[23 ]. This pathway can be inhibited by IFN-b
and IL-10, and therefore they suggested that in
leprosy pathogenesis there is an inverse correlation
between IFN-b and IFN-g expression programs and
that altering the IFN balance by blocking IFN-b or
enhancing IFN-g responses could prove to be a new
&&
therapeutic intervention [23 ].
CD163 is a monocyte/macrophage receptor that
recognizes hemoglobin–haptoglobin complexes
[24] and it has been suggested to function as an
alternative receptor for M. leprae entry into host cells
[25]. Therefore, M. leprae could induce CD163 in
order to create a favorable environment for its own
survival [25]. Data supporting this hypothesis come
from Brazil, where six lepromatous leprosy and six
borderline tuberculoid patients were compared.
Lepromatous macrophages were shown to express
higher mRNA and protein levels of the scavenger
receptor CD163, whereas increased levels of CD163
in the sera of lepromatous patients were detected
[25]. The higher expression of CD163 observed was
in parallel with the expression of the tryptophan
rate-limiting enzyme indoleamine 2,3-dioxygenase
(IDO) [25]. Hemoglobin induces the expression of
www.co-infectiousdiseases.com 415
 Tropical and travel-associated diseases
IDO in dendritic cells, supporting the interaction
between CD163 and IDO [26]. Another Brazilian
study, addressing the role of IDO in leprosy, had
demonstrated high IDO protein expression in skin
biopsies of lepromatous leprosy patients, whereas
very few IDOþ cells were seen in lesions from border-
line tuberculoid patients and patients undergoing
T1Rs [27].
&
Schenk et al. [28 ] compared the expression of
the receptor nucleotide-binding oligomerization
domain-containing protein 2 (NOD2) and IL-32
with the clinical presentation of leprosy, as NOD2þ
cells and IL-32þ cells were three and eight-fold
higher, respectively, in borderline tuberculoid than
lepromatous leprosy skin lesions. Activation of
NOD2 with its ligand muramyl dipeptide has been
shown to induce differentiation of monocytes into
& &
dendritic cells [28 ]. Conversely, Chung et al. [29 ]
studied galectin-3, a protein predominantly
expressed on cells of the monocyte/macrophage
lineage, and showed galectin-3 to be associated with
lepromatous leprosy as it was expressed strongly in
80–95% of cells in skin lesions from three leprom-
atous patients, whereas it was almost undetectable
in lesions from three tuberculoid patients, in which
only 10% of the cells were weakly galectin-3þ. How-
ever, live M. leprae did not increase the expression of
galectin-3 mRNA or protein in human monocytes.
To explain the immune unresponsiveness observed
in lepromatous patients, Chung et al. proposed that
in lepromatous lesions monocytes are promoted to
differentiate into macrophages instead of to den-
dritic cells. Therefore, if galectin-3, demonstrated to
be highly expressed in lepromatous leprosy lesions,
also promotes the differentiation of monocytes into
macrophages rather than dendritic cells, then galec-
tin-3 could potentially become a target for future
interventions promoting host defense in humans.
Pathogenesis of type 1 reactions
b-defensin 3 is an antimicrobial peptide serving as
the first line of defense against many bacteria,
viruses and fungi. A study performed by our group
looked at the association of the human b-defensin 3
&
with T1Rs [30 ]. Using real-time PCR and immuno-
histochemistry, human b-defensin 3 was induced in
&
T1Rs and suppressed by corticosteroids [30 ]. Inter-
estingly, keratinocytes, but not macrophages, upre-
gulated human b-defensin 3 in response to M. leprae
&
in vitro [30 ]. Although keratinocytes play an import-
ant role in immune homeostasis and innate immun-
ity, they are often thought as part of the barrier
rather than an immune organ. This study shows the
potential importance of epidermal processes as well
as dermal ones in the pathophysiology of leprosy.
416 www.co-infectiousdiseases.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Another study performed by our group included
21 patients with cutaneous involvement of a leprosy
T1R and showed firstly that TLR2 and TLR4 genes
and protein were expressed in lesions of T1Rs and
secondly that both gene and protein expression of
TLR2 and TLR4 were significantly reduced during
corticosteroid treatment [31]. This is the first study
to examine the expression of TLR2 and TLR4 in vivo
in individuals experiencing T1Rs and leads the way
to further research of TLRs in the pathophysiology
of leprosy reactions [31].
ADAPTIVE IMMUNITY
T cell anergy is considered a characteristic of lep-
romatous leprosy patients [32]. Recent work on the
role of T regulatory cells (Tregs) in leprosy and the
recently identified IL17-producing T helper (Th17)
cells that emerged as a new subset of T helper cells
is discussed.
T cell responses
Lsr2 is a 15kDa basic protein of M. leprae, and Lsr2
peptides were previously shown to be recognized by
T cells and antibodies of tuberculoid and leproma-
tous patients [33]. Using 22 synthetic overlapping
and end-to-end peptides spanning the Lsr2
sequence, a recent study investigated the T cell
functions measured by lymphoproliferation and
IFN-g release [34]. The study showed that anergic
lepromatous patients, who did not show in-vitro
responses to M. leprae antigens, did respond to the
multiple T cell epitopes of Lsr2 protein [34]. Another
study addressed the role of Lsr2 in eliciting lympho-
proliferation and IFN-g release during T1Rs and ENL
[35] and showed that even 6 months postreactions,
patients continued to respond to Lsr2 and its pep-
tides, suggesting that Lsr2 could be a promising
candidate disease marker in the diagnosis of leprosy
reactions [35].
T regulatory cells
A study by Palermo et al. [36] addressed the role of
Tregs in leprosy. Tregs suppress the functions of
effector T cells, but in infection this suppression
could result in reduced effectiveness of immune
response against the pathogen. Palermo et al. admit-
ted 28 consecutive newly diagnosed leprosy patients
that were dichotomized as lepromatous leprosy
(borderline lepromatous and lepromatous leprosy)
and tuberculoid leprosy patients (borderline tuber-
culoid and tuberculoid leprosy). Using flow cytom-
etry in peripheral blood mononuclear cells (PBMCs)
and immunohistochemistry in skin lesions, Palermo
Volume 26  Number 5  October 2013
 New findings in the pathogenesis of leprosy Polycarpou et al.
et al. found significant increase of Tregs in leprom-
atous patients compared with tuberculoid patients
not only in blood but also in situ [36]. Tregs were
rarely observed in tuberculoid lesions [36]. IL-10 and
cytotoxic T-lymphocyte antigen 4, but not trans-
forming growth factor-b, were increased in leprom-
atous rather than tuberculoid lesions [36]. These
results contradict a previous study that showed a
higher frequency of circulating Tregs in the periph-
eral blood of tuberculoid than lepromatous patients
[37] This study suggests that controlling the balance
of Tregs function may be a potential new strategy in
managing leprosy.
T helper 17 cytokines
IL-17 was first described as a proinflammatory cyto-
kine produced by T cells [38]. Later, it was discovered
that the cell sources of IL-17 are in fact the Th17
cells, which are developmentally distinct forms of
Th1 and Th2 cells [38]. IL-17, now referred as IL-17A,
is a member of the IL-17 family, which includes IL-
17A-F [38]. IL-17 overexpression has been associated
with diseases such as rheumatoid arthritis, psoriasis,
Crohn disease and multiple sclerosis.
The first published study on IL-17A in biopsies
from active lesions of 38 leprosy patients and 15
healthy controls demonstrated an abrogated mRNA
IL-17A response in all leprosy patients, as compared
to controls [39]. In addition, IL-17A mRNA and
IL23p19 mRNA in lepromatous leprosy patients
had an inverse linear correlation with bacteriologi-
cal index, the standard method for assessment of
M. leprae mycobacterial load based on a logarithmic
scale. The observed inverse linear correlation with
bacteriological index was not seen for the related
cytokine IL-6 [39]. However, circulating IL-17A was
undetectable in both patients and controls [39].
IL-17F acts as a mediator in the delayed-type
hypersensitivity reactions by induction of IFN-g-
inducible protein 10 in a model of airway inflam-
mation, which includes bronchial epithelial cells
[40]. IL-17F also mediates inflammatory responses
against certain intracellular pathogens [41].
Chaitanya et al. [42] analyzed the serum circulatory
levels of IL-17F in patients with T1Rs, ENL and with
nonreactional leprosy of all Ridley–Jopling types.
This Indian study included 80 active untreated lep-
rosy cases with T1R, 21 cases with ENL, 80 nonreac-
tional leprosy cases and 94 nonleprosy cases. ELISA
was used to measure the IL-17F levels in the serum.
The study demonstrated the mean serum levels of
IL-17F to be significantly higher in the T1R group
when compared with nonreactional and nonleprosy
groups [42]. More research is needed to investigate a
possible role of IL-17F as a potential biomarker of
0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
T1Rs or to demonstrate a pathogenic-causative
effect of IL-17F in leprosy complications. Interest-
ingly, although mycobacteria have been previously
reported to stimulate the production of IL-17 [43],
when samples were classified based on the bacterio-
logical index into groups, an inversely proportional
association of the IL-17F levels with the bacterio-
logical index was shown [42].
The study by Martiniuk et al. [44] investigated
the Th17 subset in skin biopsies of seven ENL
patients from Nepal treated with thalidomide for
21 days. RNA was extracted followed by RT-PCR.
Martiniuk et al. studied the relative gene expression
patterns for 20 genes in the Th17 pathway and
showed that thalidomide both suppresses some
inflammatory components of Th17, while enhanc-
ing those involved in cell-mediated immunity [44].
IL-17A, the hallmark cytokine of Th17, was detected
before and after thalidomide treatment, suggesting
that IL-17A could possibly be upregulated by thali-
domide treatment of ENL [44]. They also suggested
IDO to be investigated in the future as a potential
target of thalidomide as it was upregulated by IFN-g
in ENL, whereas it was downregulated following
thalidomide treatment of ENL [44]. IDO had been
implicated in the past as inhibiting the Th17
responses in a mouse model of Mycobacterium tuber-
culosis [45]. IDO expression has been demonstrated
to be in parallel with the expression of the receptor
CD163 [25], suggested to be an alternative receptor
for M. leprae entry into host cells [25].
MYCOBACTERIUM LEPROMATOSIS:
A NEW SPECIES CAUSING LEPROSY?
A diffuse form of lepromatous leprosy (DLL), also
known as Lucio’s leprosy, predominantly seen in
Mexico and Central America, is characterized clin-
ically by diffuse, nonnodular cutaneous infiltration
and pathologically by mycobacterial invasion of the
endothelium and vasculopathy in the dermis and
subcutis [6]. Lucio’s phenomenon may develop in
DLL patients when the skin becomes ulcerated lead-
ing to secondary bacterial infections, sepsis and
death. Lucio’s phemomenon is associated with
necrosis of arterioles.
In 2008 Han et al. [46], using genome sequenc-
ing, isolated a novel Mycobacterium species from
two Mexican patients with DLL. It was named
Mycobacterium lepromatosis and was described to
diverge from a common ancestor with M. leprae
[47]. Since then, several case reports of leprosy
patients having infection with M. lepromatosis
have been published [48–50]. Another study by
Han et al. [51] using PCR tested for M. lepromatosis
and M. leprae DNA, which was extracted from
www.co-infectiousdiseases.com 417
 Tropical and travel-associated diseases
archived skin biopsy specimens of 120 leprosy
cases from Mexico. Han et al. [51] supported
that M. lepromatosis is the main cause of leprosy
in Mexico as in their study, and it had been associ-
ated with far more leprosy cases and other clinical
forms of leprosy than DLL. In some individuals
coinfection with M. leprae and M. lepromatosis was
observed [51]. In addition, a recent study from the
same group described two Mexican leprosy
patients, one with ENL and the other with Lucio’s
phenomenon from which M. lepromatosis was iso-
lated from the lymph node tissue [52]. However,
Gillis et al. [53] have noted that the experiments and
data need confirmation to prove that M. leproma-
tosis is a new leprosy-causing species. We still do not
know whether the investigators have isolated a
variant of M. leprae or whether they have isolated
DNA from a bacterium closely related to M. leprae
that is associated with M. leprae infection but may
not cause of the disease itself [53].
CONCLUSION
Several recent studies focused on the identification
of candidate biomarkers associated with the clinical
phenotype of the disease or the occurrence of lep-
rosy reactions. New candidate proteins or biological
pathways were identified and these studies shed
light on the pathogenesis of leprosy, with possible
implications for other mycobacterial diseases.
Future studies should include more clinical samples
in order to study the ability of M. leprae to modulate
lipid metabolism, by measuring the ADRP and HSL
levels in patient samples. More research needs to be
undertaken in vivo to investigate whether M. leprae
reprograms Schwann cells and uses this mechanism
to spread to other tissues. Larger studies to identify
biomarkers and pathophysiological pathways
should use patients across the Ridley–Jopling spec-
trum. Promising candidate biomarkers have been
identified and should be further investigated
include the human IFNs and IDO/CD163 expres-
sion. Galectin-3 has also arisen as new potential
target for future interventions. More work should
clarify the role of Tregs and Th17 cytokines in
leprosy. Finally, future work should demonstrate
whether M. lepromatosis is indeed a new species
causing leprosy.
Acknowledgements
Funding source: Hospital and Homes of St Giles.
Conflicts of interest
There are no conflicts of interest
418 www.co-infectiousdiseases.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 485).
1. Britton WJ, Lockwood DN. Leprosy. Lancet 2004; 363:1209–1219.
2. World Health Organization. Global leprosy situation. World Health Organiza-
tion; 2012.
3. Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-
group system. Int J Lepr Other Mycobact Dis 1966; 34:255–273.
4. Sarno EN, Grau GE, Vieira LM, Nery JA. Serum levels of tumour necrosis
factor-alpha and interleukin-1 beta during leprosy reactional states. Clin Exp
Immunol 1991; 84:103–108.
5. Wemambu SN, Turk JL, Waters MF, Rees RJ. Erythema nodosum leprosum: a
clinical manifestation of the arthus phenomenon. Lancet 1969; 2:933–935.
6. Kahawita IP, Lockwood DN. Towards understanding the pathology of erythe-
ma nodosum leprosum. Trans R Soc Trop Med Hyg 2008; 102:329–337.
7. van Veen NH, Nicholls PG, Smith WC, Richardus JH. Corticosteroids for
treating nerve damage in leprosy. Lepr Rev 2008; 79:361–371.
8. Cruz D, Watson AD, Miller CS, et al. Host-derived oxidized phospholipids and
HDL regulate innate immunity in human leprosy. J Clin Invest 2008;
118:2917–2928.
9. Mattos KA, D’Avila H, Rodrigues LS, et al. Lipid droplet formation in leprosy:
Toll-like receptor-regulated organelles involved in eicosanoid formation and
Mycobacterium leprae pathogenesis. J Leukoc Biol 2010; 87:371–384.
10. Mattos KA, Oliveira VG, D’Avila H, et al. TLR6-driven lipid droplets in Myco-
bacterium leprae-infected Schwann cells: immunoinflammatory platforms
associated with bacterial persistence. J Immunol 2011; 187:2548–2558.
11. Imamura M, Inoguchi T, Ikuyama S, et al. ADRP stimulates lipid accumulation
and lipid droplet formation in murine fibroblasts. Am J Physiol Endocrinol
Metab 2002; 283:E775–E783.
12. Egan JJ, Greenberg AS, Chang MK, et al. Mechanism of hormone-stimulated
lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid
storage droplet. Proc Natl Acad Sci U S A 1992; 89:8537–8541.
13. Tanigawa K, Suzuki K, Nakamura K, et al. Expression of adipose differentia-
tion-related protein (ADRP) and perilipin in macrophages infected with
Mycobacterium leprae. FEMS Microbiol Lett 2008; 289:72–79.
14. Tanigawa K, Degang Y, Kawashima A, et al. Essential role of hormone-
sensitive lipase (HSL) in the maintenance of lipid storage in Mycobacterium
leprae-infected macrophages. Microb Pathog 2012; 52:285–291.
15. Degang Y, Akama T, Hara T, et al. Clofazimine modulates the expression of
lipid metabolism proteins in Mycobacterium leprae-infected macrophages.
PLoS Negl Trop Dis 2012; 6:e1936.
16. Rambukkana A, Salzer JL, Yurchenco PD, Tuomanen EI. Neural targeting of
Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain.
Cell 1997; 88:811–821.
17. Rambukkana A, Yamada H, Zanazzi G, et al. Role of alpha-dystroglycan as a
Schwann cell receptor for Mycobacterium leprae. Science 1998; 282:2076–
2079.
18. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-dependent demye-
lination by Mycobacterium leprae in the absence of immune cells. Science
2002; 296:927–931.
19. Tapinos N, Ohnishi M, Rambukkana A. ErbB2 receptor tyrosine kinase
signaling mediates early demyelination induced by leprosy bacilli. Nat Med
2006; 12:961–966.
20. Masaki T, Qu J, Cholewa-Waclaw J, et al. Reprogramming adult Schwann
&& cells to stem cell-like cells by leprosy bacilli promotes dissemination of
infection. Cell 2013; 152:51–67.
This is the first study that shows reprogramming of adult cells into stem cells with
the use of a bacterium, in specific M. leprae.
21. Liu PT, Wheelwright M, Teles R, et al. MicroRNA-21 targets the vitamin D-
dependent antimicrobial pathway in leprosy. Nat Med 2012; 18:267–273.
22. Montoya D, Cruz D, Teles RM, et al. Divergence of macrophage phagocytic
and antimicrobial programs in leprosy. Cell Host Microbe 2009; 6:343–353.
23. Teles RM, Graeber TG, Krutzik SR, et al. Type I interferon suppresses type II
&& interferon-triggered human antimycobacterial responses. Science 2013;
339:1448–1453.
This study suggests that the relative expression of IFNs at the site of infection
determines the outcome of the host response in leprosy.
24. Moller HJ, Peterslund NA, Graversen JH, Moestrup SK. Identification of the
hemoglobin scavenger receptor/CD163 as a natural soluble protein in
plasma. Blood 2002; 99:378–380.
25. Moura DF, de Mattos KA, Amadeu TP, et al. CD163 favors Mycobacterium
leprae survival and persistence by promoting anti-inflammatory pathways in
lepromatous macrophages. Eur J Immunol 2012; 42:2925–2936.
26. Ogasawara N, Oguro T, Sakabe T, et al. Hemoglobin induces the expression
of indoleamine 2,3-dioxygenase in dendritic cells through the activation of
PI3K, PKC, and NF-kappaB and the generation of reactive oxygen species.
J Cell Biochem 2009; 108:716–725.
Volume 26  Number 5  October 2013

27. de Souza Sales J, Lara FA, Amadeu TP, et al. The role of indoleamine 2, 3-
dioxygenase in lepromatous leprosy immunosuppression. Clin Exp Immunol
2011; 165:251–263.
28. Schenk M, Krutzik SR, Sieling PA, et al. NOD2 triggers an interleukin-32-
& dependent human dendritic cell program in leprosy. Nat Med 2012; 18:555–
563.
This study shows that expression of NOD2 and IL-32 at the site of leprosy infection
is greater in patients with limited as compared to progressive leprosy.
29. Chung AW, Sieling PA, Schenk M, et al. Galectin-3 regulates the innate
& immune response of human monocytes. J Infect Dis 2013; 207:947–956.
This study shows that expression of galectin-3 is associated with lepromatous
leprosy.
30. Cogen AL, Walker SL, Roberts CH, et al. Human beta-defensin 3 is up-
& regulated in cutaneous leprosy type 1 reactions. PLoS Negl Trop Dis 2012;
6:e1869.
This is the first study that shows upregulation of b-defensin 3 by M. leprae in
keratinocytes but not in macrophages and leads to future work on the interactions
between keratinocytes and M. leprae.
31. Walker SL, Roberts CH, Atkinson SE, et al. The effect of systemic corticos-
teroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4
in the cutaneous lesions of leprosy Type 1 reactions. Br J Dermatol 2012;
167:29–35.
32. Kaplan G, Weinstein DE, Steinman RM, et al. An analysis of in vitro T cell
responsiveness in lepromatous leprosy. J Exp Med 1985; 162:917–929.
33. Laal S, Sharma YD, Prasad HK, et al. Recombinant fusion protein identified by
lepromatous sera mimics native Mycobacterium leprae in T-cell responses
across the leprosy spectrum. Proc Natl Acad Sci U S A 1991; 88:1054–1058.
34. Chaduvula M, Murtaza A, Misra N, et al. Lsr2 peptides of Mycobacterium
leprae show hierarchical responses in lymphoproliferative assays, with se-
lective recognition by patients with anergic lepromatous leprosy. Infect Immun
2012; 80:742–752.
35. Saini C, Prasad HK, Rani R, et al. Lsr2 of Mycobacterium leprae and its
synthetic peptides elicit restitution of T cell responses in erythema nodosum
leprosum and reversal reactions in patients with lepromatous leprosy. Clin
Vaccine Immunol 2013; 20:673–682.
36. Palermo ML, Pagliari C, Trindade MA, et al. Increased expression of regulatory
T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med
Hyg 2012; 86:878–883.
37. Attia EA, Abdallah M, Saad AA, et al. Circulating CD4þ CD25 high FoxP3þ T
cells vary in different clinical forms of leprosy. Int J Dermatol 2010; 49:1152–
1158.
38. Miossec P. IL-17 and Th17 cells in human inflammatory diseases. Microbes
Infect 2009; 11:625–630.
0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New findings in the pathogenesis of leprosy Polycarpou et al.
39. da Motta-Passos I, Malheiro A, Gomes Naveca F, et al. Decreased RNA
expression of interleukin 17A in skin of leprosy. Eur J Dermatol 2012;
22:488–494.
40. Kawaguchi M, Kokubu F, Huang SK, et al. The IL-17F signaling pathway is
involved in the induction of IFN-gamma-inducible protein 10 in bronchial
epithelial cells. J Allergy Clin Immunol 2007; 119:1408–1414.
41. Khader SA, Gopal R. IL-17 in protective immunity to intracellular pathogens.
Virulence 2010; 1:423–427.
42. Chaitanya S, Lavania M, Turankar RP, et al. Increased serum circulatory levels
of interleukin 17F in type 1 reactions of leprosy. J Clin Immunol 2012;
32:1415–1420.
43. Zenha EM, Wambier CG, Novelino AL, et al. Clinical and immunological
evaluation after BCG-id vaccine in leprosy patients in a 5-year follow-up study.
J Inflamm Res 2012; 5:125–135.
44. Martiniuk F, Giovinazzo J, Tan AU, et al. Lessons of leprosy: the emergence of
TH17 cytokines during type II reactions (ENL) is teaching us about T-cell
plasticity. J Drugs Dermatol 2012; 11:626–630.
45. Desvignes L, Ernst JD. Interferon-gamma-responsive nonhematopoietic cells
regulate the immune response to Mycobacterium tuberculosis. Immunity
2009; 31:974–985.
46. Han XY, Seo YH, Sizer KC, et al. A new Mycobacterium species causing
diffuse lepromatous leprosy. Am J Clin Pathol 2008; 130:856–864.
47. Han XY, Sizer KC, Thompson EJ, et al. Comparative sequence analysis of
Mycobacterium leprae and the new leprosy-causing Mycobacterium lepro-
matosis. J Bacteriol 2009; 191:6067–6074.
48. Vera-Cabrera L, Escalante-Fuentes WG, Gomez-Flores M, et al. Case of
diffuse lepromatous leprosy associated with ‘Mycobacterium lepromatosis’. J
Clin Microbiol 2011; 49:4366–4368.
49. Yang Han X, Clement Sizer K, Tan HH. Identification of the leprosy agent
Mycobacterium lepromatosis in Singapore. J Drugs Dermatol 2012; 11:168–
172.
50. Jessamine PG, Desjardins M, Gillis T, et al. Leprosy-like illness in a patient with
Mycobacterium lepromatosis from Ontario, Canada. J Drugs Dermatol 2012;
11:229–233.
51. Han XY, Sizer KC, Velarde-Felix JS, et al. The leprosy agents Mycobacterium
lepromatosis and Mycobacterium leprae in Mexico. Int J Dermatol 2012;
51:952–959.
52. Han XY, Jessurun J. Severe leprosy reactions due to Mycobacterium lepro-
matosis. Am J Med Sci 2013; 345:65–69.
53. Gillis TP, Scollard DM, Lockwood DN. What is the evidence that the putative
Mycobacterium lepromatosis species causes diffuse lepromatous leprosy?
Lepr Rev 2011; 82:205–209.
www.co-infectiousdiseases.com 419