Clinics in Dermatology (2015) 33, 4654

Mechanisms of nerve injury in leprosy

David M. Scollard, MD, PhD a,, Richard W. Truman, PhD b , Gigi J. Ebenezer, MBBS, MD c
a

Director, National Hansens Disease Programs, Baton Rouge, Louisiana

Laboratory Research Branch, National Hansens Disease Programs at LSU, Baton Rouge, Louisiana
c
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland
b

Abstract All patients with leprosy have some degree of nerve involvement. Perineural inflammation is
the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of
Mycobacterium leprae into nerves. Once inside nerves, M leprae are ingested by Schwann cells,
with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected
nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been
greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo
provides the only animal model of the pathogenesis of M leprae infection. New tools available for this model
enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve
trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both
neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of
nerve injury in leprosy and offers a means of testing proposed interventions.
Published by Elsevier Inc.

Introduction
Nerve involvement occurs in all patients with leprosy.
The earliest definitive clinical sign of this disease is
hypoesthesia in a cutaneous lesion. In skin biopsy specimens, perineural inflammation is the histopathologic hallmark of leprosy (Figure 1), and because Mycobacterium
leprae is the only bacterium that infects nerves and Schwann
cells (SC), the demonstration of acid-fast bacilli within a
peripheral nerve is pathognomonic (Figure 1). These
observationsSC infection and perineural inflammation
comprise the two major concepts around which nerve injury
in leprosy is understood and are the primary foci of research
into the mechanisms of nerve injury in leprosy.1 A third,

Supported in part by the Department of Health and Humans Services,

Health Resources and Services Administration, Healthcare Systems Bureau,
National Hansens Disease Program and National Institute of Allergy and
Infectious Diseases (NIAID IAA-2646).
Corresponding author. Tel.: +1-225-756-3713; fax: + 1-225-756-3819.
E-mail address: dscollard@hrsa.gov (D.M. Scollard).

http://dx.doi.org/10.1016/j.clindermatol.2014.07.008
0738-081X/Published by Elsevier Inc.

newer focus of research is the study of epidermal nerve fibers

in this disease.
Mycobacterium leprae is an obligate intracellular organism that prefers a cool growth temperature (Table),
influencing the location of clinical lesions to cooler areas
of the body.2 Approximately 95% of adults have native
immunity to M leprae3 and will not become infected even
with substantial exposure. After infection with M leprae,
nerves are apparently infected very early in the course of this
disease, possibly before a cellular immune response (CMI)
has developed.
The immunopathologic spectrum of leprosy2,4 is recapitulated in nerves (Figure 1): In polar tuberculoid disease (TT),
bacilli are rare because the hosts CMI response to M leprae
is strong, and well-organized granulomas may replace the
entire nerve. In polar lepromatous disease (LL) the hosts
CMI to M leprae is ineffective and, in nerves as elsewhere,
the bacterial load is extremely high and the inflammatory
response within the nerve is a disorganized collection of
histiocytes with foamy cytoplasm. Between these two polar
forms of leprosy is a wide borderline region, further
subdivided into borderline tuberculoid (BT), mid-borderline

Nerve injury in leprosy

47

Fig. 1 Inflammation and infection of cutaneous nerves across the leprosy spectrum. The inflammatory responses in and around cutaneous nerves
are shown in the upper panel; arrows highlight recognizable nerve twigs. The immunopathologic classifications of leprosy, TT to LL, are indicated
at the top of the figure (see text; mid-borderline, BB, is not shown). The TT lesion (upper left) is composed of a well-organized epithelioid
granuloma that has nearly destroyed the nerve, remnants of which are shown by S-100 staining. The granulomatous inflammatory response
becomes less organized across the spectrum until, at the LL extreme, it is composed of disorganized aggregates of foamy histiocytes, seen here
surrounding a nerve (upper right). (TT: S-100, original magnification 10; BT, BL, LL: hematoxylin-eosin, original magnification 250.) The
demonstration of acid-fast bacilli within nerves is pathognomonic of leprosy. In the lower panel, Fite-stained sections reveal the
corresponding intensity of M leprae infection in cutaneous nerves across the spectrum. M leprae are rare and difficult to demonstrate in
nerves of TT and BT lesions; they have been photographically enlarged in the insets. In contrast, bacilli are abundant and easily recognized in
BL and LL lesions. (Fite/methylene blue, original magnification 1000.)

(BB), and borderline lepromatous (BL).5 Slowly progressive, insidious, silent neuropathy occurs in patients with all
forms of leprosytuberculoid, borderline, and lepromatous.
Acute neuritis develops in some patients and often also
accompanies the immunologic complications of leprosy
called reactions. Reactions are episodes of sudden,
unexplained, spontaneous enhancement of an individuals
immune response to M leprae, and the immunologic
mechanisms that characterize them in the skin may also
occur in nerves.1 This review will focus on the pathogenesis
of nerve injury in leprosy not related to reactions, because
reactions have been reviewed elsewhere.6,7

Early changes in nerves

Axonal atrophy, measured as reduction in axon caliber,
has been described in nerves of leprosy patients.8 The
pathogenesis of this atrophy is not clear, but abnormalities of
phosphorylation of neurofilament proteins have been observed
in nerves from treated and untreated patients with different
types of leprosy and in nerves with inflammation varying from
minimal to extensive.9 This has been investigated in a mouse
model, in which hypophosphorylation of neurofilament

proteins was observed in noninfected sciatic nerves of mice

inoculated with M leprae in the hind footpads.10 These
findings suggest that M leprae may initiate early biochemical
changes in the axonal compartment, preceding structural
changes in myelinated fibers.

M leprae entry into nerves

Perineural inflammation in leprosy, a dermatopathologic
pearl, may provide clues to the route by which M leprae
enters nerves. M leprae infection of endothelial cells is well
documented in human leprosy11; studies in the armadillo
model of leprosy (Table) indicate that these organisms collect
in epineurial lymphatics and from there are able to infect the
blood vessels of the epineurium.12 Inflammation develops
around foci of infection, and classical studies in leprosy
determined that this inflammation ascends proximally from
cutaneous lesions to subcutaneous nerves to nerve trunks.13,14
The endothelial location offers a vascular route of entry for
M leprae through the impermeable perineural sheath and into
the endoneurial compartment, possibly carried within macrophages.15 Such a mechanism of entry into nerves does not
postulate any role for specific immunologic activities but is

48
Table

D.M. Scollard et al.

Challenges and possibilities in experimental investigation of nerve injury in leprosy
M leprae

Tissue culture

Culture of
M leprae
Multiplication of
M leprae

Cannot be cultivated on
artificial media
Doubling time = 13 days;
Optimal growth at 32oC

M leprae survive within

Limited growth in footpads
cells; cannot assess growth
Most cells in culture die or Mouse experiments require
divide in b 13 days
months or years to complete

Determination
of viability of
M leprae
Killing of M leprae

Viability cannot be
determined by growth
on agar, etc.
Killed by freeze-thaw

Study of effects of
viable organisms

Viable bacilli must be

obtained fresh from
infected tissues (mouse
or armadillo)
Genome has been
sequenced
Mutations associated
with drug resistance
have been identified

Genomics
Mutations

Modeling
M lepraenerve
interaction

n/a

Suitability for
translational
studies

n/a

Mouse

Armadillo

Disseminated infection
develops
Armadillo experiments
require months or years
to complete
Radiorespirometry; fluorescent methods for live/dead bacilli; RNA-based methods
being developed

M leprae die rapidly at

temperature N 35oC
Standard cell culture
conditions (37oC) do not
simulate infection with
viable bacilli
Genome known for cells
used in tissue culture
Immortalized cells are
genetically abnormal;
may not replicate some
normal functions
Schwann cells and SC/axon
co-culture models
are available
Minimal

probably mediated by adherins or similar nonimmunologic

mechanisms involving endothelial cells.

Schwann cells
Once inside the fascicle, M leprae is ingested by SC. The
extraordinary spectacle of acid-fast bacilli within SC has
captured the imagination of investigators for decades.
Although direct study of affected human nerves is difficult,
SC can be studied in tissue culture, and so they have offered a
ready model to study M leprae infection in vitro (Table),
which has generated a large literature of its own.
Several molecules have been identified that are responsible for M lepraes adherence to and ingestion by SC. 16,17
Once inside SC, M leprae has a viability profile similar to
that in macrophages (the more common host cell).18 Both
myelinating and nonmyelinated Schwann cells may be
infected, but M leprae is a very well adapted, minimally
toxic pathogen, capable of inhabiting various cells without
marked injury or dysfunction. The general morphology of
Schwann cells is not altered by infection in vitro, and their
basic ability to interact with axons and produce myelin is
not impaired. 18

Growth in footpads
(cooler site)
M leprae viability high;
limited proliferation of
bacilli in footpads

Good growth (core body

temp = 32oC)
M leprae viability high;
infection progresses and
becomes disseminated

Genome has been

sequenced
Gene knockout
mice available

Genome has been

sequenced
Molecular probes are
being developed for
cytokines, etc.

M leprae does not infect

nerves in mice; knockout
mice enable modeling of
some aspects
Footpad infection may
initiate biochemical
changes in regional nerves

M leprae does infect

nerves in armadillos;
recapitulates many features
of human infection
Neurophysiologic studies
possible; can study effects
of drug interventions on
sensory fibers in skin punch
biopsy specimens

Some SC functions may be different in lepromatous than in

tuberculoid patients. The foamy appearance of infected SC in
lepromatous nerves is due to lipid droplets, microorganelles
recruited into M lepraecontaining phagosomes by M leprae
through Toll-like receptor-6dependent signaling.19 In
lepromatous patients, these lipid droplets may facilitate
persistence of M leprae in SC. Schwann cells infected
in vitro are also able to present antigen and can serve as
targets for primed cytotoxic T cells.20,21 If this occurs in human
disease (which has not been confirmed), it would apply to
tuberculoid patients who develop CMI to M leprae but would
probably have little or no application in lepromatous patients
who do not produce M lepraespecific T cells.
Ultimately, individual neurons in leprosy undergo
segmental demyelination.22,23 Demyelination may be induced by a variety of insults, including high levels of some
proinflammatory cytokines.2426 The major toxic effector
molecule known to kill M leprae is nitric oxide (NO), and
NO has been demonstrated in the inflammatory infiltrates of
nerves in leprosy lesions.27 Nitrotyrosine, an end product of
the metabolism of NO, has also been observed in nerves in
BL lesions, and this molecule has been associated with lipid
peroxidation of myelin leading to demyelination of nerves in
other diseases.28,29 M leprae also bind and activate the
tyrosine kinase receptor ErbB2, which induces the Erk1/2

Nerve injury in leprosy

signal transduction pathways. In experimental systems this
can result in demyelination and dedifferentiation of the
terminally differentiated Schwann cell.3032 No evidence is
yet available to indicate if this sequence of events occurs in
human leprosy.
Schwann cells are clearly at the center of the pathogenesis
of nerve injury in leprosy; however, it is not clear how much
of this is due to the fact that some SC are infected and how
much is due to the toxic inflammatory milieu within and
around these nerves.

Perineural inflammation
The extent to which the various observations in vitro are
actually occurring in vivo is not clear, however, and such
in vitro studies do not replicate the immune and inflammatory milieu of the infected peripheral nerve. To validate and
extend such findings, mechanisms must be examined in the
human patient or tested in an experimental animal model. For
practical and ethical reasons, peripheral nerves are rarely
biopsied in humans. When diagnostic biopsies are done, the
sural or radial cutaneous nerves are selected because biopsy
of either of these sensory nerves will not cause motor
impairment; however, these nerves may not be significant
foci of infection, and inferences about mechanisms from
studies of such biopsies must be made cautiously.
Dermal macrophages within inflammatory infiltrates are
the major host cells for M leprae. This chronic, persistent
inflammation in cutaneous leprosy lesions may lead to
destruction of dermal appendages such as sebaceous and
sweat glands, leading to dryness of affected skin and to
destruction of hair follicles, causing madarosis, for example.
Cutaneous nerves may be injured by the same inflammatory
processes. The well-organized granulomatous responses in
tuberculoid disease may function aggressively to destroy
adjacent structures, but even in lepromatous patients, with
ineffective CMI, chronic inflammation will ultimately
destroy surrounding tissue, including nerves.
Edema regularly accompanies cutaneous leprosy lesions,
and it has been invoked as a potential mechanism of injury to
peripheral nerves. Endoneurial edema can cause peripheral
nerve injury by various mechanisms and has been explored
in several models.33 The immunoinflammatory milieu of
nerves in leprosy, especially during reactions, could lead to
edema and transient pressure increases causing intermittent
ischemia, possibly comparable to that seen in models of
ischemia-reperfusion injury. 34 This has not yet been
demonstrated in biopsy specimens or in animal models of
leprosy neuropathy. No measurements of endoneurial
pressure have been done in leprosy to document increased
pressure or edema, although surgeons who operate on
patients with acute lepromatous neuritis describe the
procedures as decompression.35 Notably, available data
do not provide support for the value of this surgery,36

49
probably due to problems in study design. In any case, edema
seems an unlikely mechanism for the chronic, painless,
silent nerve injury that is common in leprosy patients,
including those who do not have reactions.

Evidence from human nerve biopsies

Very limited molecular data are available regarding
immunologic or neural mediators in leprosy-affected human
nerves because nerves are seldom biopsied. The levels of
tumor necrosis factor (TNF) in skin and nerves of leprosy
lesions were similar in one study,37 suggesting that the
immunologic phenomena studied extensively in leprosy skin
lesions also apply to nerves. A larger study confirmed these
observations and also found substantial amounts of transforming growth factor (TGF-) and inducible nitric oxide
synthase (iNOS) in nerve fibers by immunohistochemistry. 38
Other elegant immunohistochemical studies have revealed high levels of matrix metalloproteinases (MMP) 2
and MMP-9 within both inflamed and noninflamed nerves
from leprosy patients. These MMPs appeared to be produced
by SC and intraneural macrophages, and the highest levels of
MMPs were observed in nerves with endoneurial inflammation.39,40 Such MMPs may play a role in demyelination41
and contribute to the neuroinflammatory response in many
diseases of the central nervous system.42 Other studies have
examined the mRNA and protein levels of Ninjurin-1, an
adhesion molecule involved in response to injury and
regeneration in peripheral nerves. Both mRNA upregulation
and elevated levels of the protein were observed in nerve
biopsy specimens from leprosy patients with neuritis.43
Studies of human nerve biopsies are difficult for many
reasons, and the duration of infection and nerve involvement
before study cannot be clearly defined. To obtain such
information, an animal model is required.

Armadillo model
The nine-banded armadillo (Dasypus novemcinctus) is
the only other natural host for M leprae44 (Table). Nave
armadillos can be experimentally infected and offer the only
model of leprosy in an immunologically intact mammal.
Infection of nerves was recognized when the susceptibility of
this animal to M leprae was first described,45,46 and
dissections of peripheral nerves in infected animals demonstrated that the infection of nerves in armadillos recapitulates
many features of the human host.11,47
Armadillos do not reliably respond to thermal, light, or
tactile nociceptive stimulants, but measurement of nerve
conduction can be used effectively to assess function of their
motor nerves. Demyelinating events result in a decreased
nerve conduction velocity (NCV) measured in m/s, whereas
axonal loss and muscular atrophy lead to a decrease in

50

D.M. Scollard et al.

Fig. 2 Gene expression profiling of posterior tibial nerves from nave, M lepraeinfected untreated and treated armadillos. Alteration in
expression of genes was observed armadillos in comparisons of posterior tibial nerves from (1) nave, uninfected, normal animals; (2) infected
untreated animals; and (3) infected, treated animals that had received 12 months of rifampin. Genes analyzed were those associated with
maintenance of neurons, such as PGP9.5 (UCHL1), PMP 22, -tubulin, and neurofilament (NCAM); nerve growth factors such as NGF- and
DLK-1; and inflammation (tumor necrosis factor [TNF-] and interferon [IFN-]). Relative expression was computed by using the Ct
method and data were normalized using GAP3DH. Results represent mean SD from duplicate experiments on five animals in each group.

the compound motor action potential (CMAP) measured in

mV.48 Conduction deficits have been observed in the
posterior tibial nerves of 75% of all experimentally infected
armadillos, with onset occurring as early as 90 days
postinfection. Similar to observations on humans, depressed
compound motor action potential amplitude (b 0.9 mV) is the
most common presentation, but abnormal nerve conduction
velocity (b 40 m/s) also can be observed.49,50 Most armadillos
progress from normal conduction to a total conduction block
by the latest stages of their experimentally induced infections
with M leprae. Onset of conduction abnormality generally
coincides with evolution of a detectable immune response to
M leprae and is a significant predictor of other nonspecific
symptoms of clinical neuropathy such as plantar ulcers and
nail avulsion or hypertrophy.

Molecular studies of armadillo nerves

Nerve segments obtained at necropsy from armadillos
enable extensive assessment of gene transcripts in M leprae
infected and noninfected nerves at a defined duration of
infection. Cross-species hybridization using human gene
chips has revealed a total of 4313 differentially regulated
genes (a greater than fourfold change) in the nerve of latestage (N 2 years) infected armadillos. This gene expression
profile includes genes pertaining to antigen processing and
presentation, apoptosis, cell adhesion, cell migration, cell
proliferation, cellular trafficking, chemotaxis, degeneration,
growth factors, and inflammation, as well as neuronal
degeneration and regeneration activities in infected armadillo

nerves.49 In addition, the recently available whole genome

sequence has enabled us to design armadillo-specific
quantitative reverse transcriptasepolymerase chain reaction
(RT-PCR) assays. Genes associated with inflammation
(interferon [IFN-], TNF-) and constitutive neuroproteins (protein gene product 9.5 [PGP9.5], -tubulin,
neurofilament) were found to be upregulated, and growth
factors (DLK-1, nerve growth factor [NGF-]) required
for regeneration in the peripheral nervous system51 were
downregulated in affected nerves (Figure 2). Further studies
of armadillo nerves are likely to elucidate much about the
mechanisms of nerve injury in leprosy and enable potential
new interventions to be assessed before clinical trials.

Epidermal nerve fiber and Schwann cell density

Tactile sensitivity is mediated by thickly myelinated A
fibers of the dermis, whereas thermal sensitivity is mediated
by thin myelinated A fibers and unmyelinated C type fibers
that end in epidermis as free nerve endings.52 Some evidence
suggests that the C fibers in the epidermis are the earliest to
undergo degeneration in leprosy, consistent with clinical
observations indicating that the assessment of thermal
sensation is probably the primary component in establishing
early diagnosis.53,54
Immunostaining of punch skin biopsy specimens for
PGP9.5, a neuronal pan-axonal marker, has been used by
several investigators to visualize the intraepidermal nerve
fibers and dermal nerves and antibodies to NGF receptor p75
to identify Schwann cells. Enumeration of these cells and
fibers can identify small nerve fiber impairment that is not

Nerve injury in leprosy

51

Fig. 3 Epidermal nerve fibers and Schwann cells in armadillo skin. Skin sections from nave animals, immunostained with anti-PGP9.5, a
neuronal marker, reveal dense epidermal innervation of the ear lobe (A) and abdomen (B) compared with the distal leg (C). Confocal imaging of a
skin section from the distal leg (D) demonstrates dermal axons (red; anti-PGP9.5) and Schwann cells (green; antinerve growth factor receptor,
p75) counter-stained with DRAQ5 for nuclear staining (blue). The deep dermal neurovascular bundles with nerve bundles (red arrow) and
Schwann cells (green arrow) exhibit co-localization of staining (yellow) demonstrating nerves ensheathed by Schwann cells. (Scale bar: A, B, and
C = 50 m, D = 20 m).

detected by nerve conduction tests. For example, a decrease

in epidermal density in the distal leg has been demonstrated
in sensory neuropathies associated with diabetes, HIV, and
idiopathic small fiber sensory neuropathies.5558 Although
leprosy neuritis has been well described clinically and
histologically, very little morphologic work has been done to
detect early damage to sensory nerves.
In nave armadillos, quantitation of epidermal fibers in
skin biopsies of ears, abdomen, and a distal leg has shown
a length-dependent innervation similar to humans 59
(Figure 3). The infected animals showed a lower mean
epidermal nerve fiber density (ENFD) compared with nave
animals, suggesting early small fiber degeneration. Double
staining of cutaneous axons and Schwann cells in nave
armadillos also mimicked the human cutaneous nerve
network pattern (Figure 3). Preliminary studies of SC
dermal cutaneous nerves in infected armadillos showed a
trend toward increasing density (unpublished) and thus
provide indirect evidence that during early infection SC
may proliferate while harboring M leprae. These studies
indicate the feasibility of studying small fibers and early
infection in the armadillo using this technique and the
possibility of using it as a novel tool to test new drugs and
therapeutic interventions. (See Figs. 2 and 4).

Effects of treatment on nerve injury in the

armadillo model
The effects of treatment on nerve injury in leprosy can
also be studied in the armadillo. In one study, nerves were
obtained from armadillos that were infected for 12 months
followed by treatment for another 12 months, and from
control animals infected for 24 months but not treated (five
animals per group). The treated group received 10 mg/kg
rifampin orally once monthly for 12 months. Nerve trunks
from treated and untreated animals were divided into distal
and proximal portions and processed for simultaneous DNA
and RNA extraction. The total number of leprosy bacilli in
each nerve was enumerated using an M lepraespecific
quantitative PCR assay targeting the RLEP gene and
normalized per centimeter of nerve. Although each of the
treated animals showed clinical improvement in skin lesions
and ulcers as a result of the antimicrobial therapy,
examination of their posterior tibial nerves showed continued
presence of M leprae (Figure 4).60
The number of viable bacilli was calculated using a
quantitative RT-PCR assay targeting 16S rRNA.61 The
results indicated that the organisms had been effectively

52

Fig. 4 Comparison of M leprae-infected armadillo posterior tibial

nerves among treated and untreated animals. Bars indicate the mean
and standard deviation of the number of M leprae per centimeter of the
posterior tibial nerves obtained at sacrifice 24 months after infection.
Treated animals had received once-monthly oral rifampin (10 mg/kg)
for 12 months. Nerve trunks were divided into distal and proximal
portions and processed for simultaneous DNA and RNA extraction.
Bacilli were enumerated using an M lepraespecific quantitative PCR
assay targeting the RLEP gene and normalized per centimeter of
nerve. Untreated armadillos had higher overall numbers of M leprae
in nerves, but treated animals also retained large numbers of dead M
leprae in their nerves even after 1 year of treatment. Although no
viable bacilli were detected after 1 year of rifampin treatment, up to
10E + 04 dead bacilli/cm nerve were still present in the nerves of
treated armadillos. Bacterial counts were significantly higher (p b .05)
in segments of the distal half compared with the proximal half
of posterior tibial nerve from untreated animals with active infection
(p = .0023) as well as after treatment (p = .01).

killed by rifampin therapy; however, bacterial counts

averaging 104 -5 bacilli per cm of nerve were still observed
even after the conclusion of a full year of treatment.
This experimental finding parallels the very slow decline
of dead M leprae in skin biopsy specimens of human leprosy
lesions, which may demonstrate the presence of dead bacilli
for years after they have been killed by antimycobacterial
therapy.62 The continued presence of dead M leprae provides
a continuing source of antigenic stimulation and may be a
major factor in the immunopathogenesis of long-term nerve
injury in leprosy.63

Conclusions
In summary (the natural sequence of these events is
not certain):
Biochemical changes such as hypophosphoryation of
axonal neurofilaments may occur soon after infection
with M leprae.
M leprae appears to enter the innermost compartment of
nerves via the blood supply and endothelium.

D.M. Scollard et al.

Several different molecules on Schwann cells bind
M leprae and facilitate its ingestion.
Epidermal nerve fibers are damaged and destroyed; some
SC are infected and some proliferate.
M leprae live and proliferate within SC.
Stimulated by M leprae, SC produce several proteins that
may contribute to demyelination.
Infected nerves are physically at the center of chronic
inflammation and immunologic activity that may persist
for many years.
Some immune and inflammatory mediators are toxic to
nerves and promote demyelination.
Segmental demyelination occurs, regeneration follows
in some fascicles, and these processes may coexist
for years
After killing of M leprae with rifampin, a large number of
dead bacterial cells remain within the nerve and may
continue to elicit immunologic responses and acute and
chronic neuritis.
Identifying the mechanisms of nerve injury in leprosy is
particularly challenging, because the major peripheral nerves
affected in humans can seldom be biopsied and studied. The
singular difficulties posed by this pathogen and by the
unusual animal models available have been reviewed. In
spite of these difficulties, extraordinary progress has been
made in the last decade, in large part due to new tools
resulting from the sequencing of the M leprae genome and
that of the only animal model of leprosy neuropathy, the
nine-banded armadillo.

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