Mycobacterium leprae-induced demyelination: a model for
early nerve degeneration
Anura Rambukkana
The molecular events that occur at the early phase of many
demyelinating neurodegenerative diseases are unknown. A recent
demonstration of rapid demyelination and axonal injury induced
by Mycobacterium leprae provides a model for elucidating the
molecular events of early nerve degeneration which might be
common to neurodegenerative diseases of both infectious origin
and unknown etiology. The identification of the M. leprae-targeted
Schwann cell receptor, dystroglycan, and its associated
molecules in myelination, demyelination and axonal functions
suggests a role for these molecules in early nerve degeneration.
Addresses
The Rockefeller University, Bronk building, Room 501,
1230 York Avenue, New York, New York 10021, USA
e-mail: rambuka@imap.rockefeller.edu
Current Opinion in Immunology 2004, 16:511–518
This review comes from a themed issue on
Host–pathogen interactions
Edited by Tom Ottenhoff and Michael Bevan
Available online 15th June 2004
0952-7915/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2004.05.021
Abbreviations
CNS central nervous system
DRP2 dystroglycan-related protein 2
G globular
GBS Guillain-Barre syndrome
LCMV lymphocytic choriomeningitis virus
LL lepromatous leprosy
MS multiple sclerosis
PGL-1 phenolic glycolipid-1
PNS peripheral nervous system
Introduction
An important challenge in therapeutic interventions for
demyelinating neurodegenerative diseases is to under-
stand the cellular and molecular events that underlie the
different phases of the disease. However, the molecular
events that occur during the early phase of neurodegen-
erative diseases are unknown, mainly because the etiol-
ogy or the trigger that initiates the disease processes have
not been identified and, therefore, it is almost impossible
to dissect the underlying mechanisms of the early phase
of these diseases.
In the mammalian nervous system, the rapid conduction
of action potentials depends on the myelin sheath, a
www.sciencedirect.com
specialized organelle, which forms a multi-lamellar struc-
ture around axons [1]. Myelin is produced by oligoden-
drocytes and Schwann cells, supporting glial cells of the
central and peripheral nervous systems (CNS and PNS),
respectively [1–3]. In myelinated nerve fibers, myelin is
arranged in segments separated by the nodes of Ranvier,
where voltage-gated sodium channels are clustered in
high density in the axon membrane so that they can
produce action potentials via saltatory conduction (the
action potentials jump from node to node; [4–6]). The
bulk of the myelin sheath is formed of compact myelin,
which covers and masks the internodal areas of the axon
comprised of fewer sodium channels and a higher density
of potassium channels, which tends to oppose the gen-
eration of action potentials [4–6]. The crucial role of
myelination of axons in nervous system functions is
evident from the large number of neurological diseases
that occur as a result of demyelination.
Demyelination is a common pathological feature of
neurodegenerative diseases of both infectious origin, such
as leprosy, and unknown etiology, such as multiple sclero-
sis (MS) and Guillain-Barre syndrome (GBS) in the CNS
and PNS, respectively [7–11]. One of the classical exam-
ples of infectious neurodegenerative diseases with per-
ipheral nerve degeneration/neuropathies is leprosy,
which is caused by the non-toxic/non-cytolytic bacterium
Mycobacterium leprae [7]. Nerve damage caused by leprosy
comprises both demyelinating neuropathies and axonal
neuropathies [7,8]. Whereas the former causes deleter-
ious effects that originate primarily in myelinating
Schwann cells, in the latter, neurons (axons), particularly
sensory neurons, are initially affected. Damage to the
myelin sheath is accompanied by a decrease in action-
potential conduction velocity, a physiological hallmark of
demyelination [2,9]. In the case of MS, the diagnosis rests
in part on the demonstration of such conduction velocity
[2,9]. Although demyelinating diseases are generally
thought of as those in which myelin is primarily affected,
subtle changes in the axon may also have profound effects
on glial cell function, myelin maintenance and subse-
quent remyelination [9,10]. Therefore, similar to the
impairment seen in MS sufferers, neurological impair-
ment in many other demyelinating diseases may also be
associated with axonal degeneration [10]. Interestingly,
somewhat similar pathological features have also been
observed in leprosy patients with peripheral nerve
damage [7,8]. Disabilities as a result of nerve damage
may be partly due to such M. leprae-induced demyelina-
tion and axonal injuries. A correlation between inflam-
matory reactions and demyelination/axonal damage has
Current Opinion in Immunology 2004, 16:511–518
512 Host–pathogen interactions
been observed in MS, GBS and leprosy [8,10,11].
However, it is largely unknown whether other non-
immune-mediated mechanisms are involved in myelin
damage and axonal degeneration in these diseases.
This review analyzes the potential mechanisms involved
in M. leprae-induced demyelination as a model represent-
ing the early phase of nerve degeneration, and how
M. leprae may use such an early nerve injury response
as a strategy for intracellular survival.
Common themes at the onset of
demyelination: M. leprae as a model
As demyelination is a common neuropathological feature
of leprosy, MS and GBS, and there are certain structural
and functional similarities between the organization of
the myelinated axons of the CNS and PNS [4,5], it is
reasonable to believe that there may be a common theme
at the onset of demyelination. Neurotrophic pathogens,
particularly those that do not cause direct cell lysis or
cytopathic effect, can be used as models in dissecting
early events of demyelination.
Recent studies have shown that both demyelination and
axonal injury can occur at the onset of M. leprae infection
in the absence of immune cells [12]. Although immune
responses play a critical role in the clinical manifestation
of the disease, the identification of non-immune-
mediated demyelination induced by M. leprae proposes
the existence of alternative mechanism(s) for demyelina-
tion. These studies have shown that the binding of
M. leprae to myelinated Schwann cell axon units is suffi-
cient to induce demyelination without causing apoptosis
or cell death of Schwann cells or neurons [12]. Thus, it is
likely that perturbation of homeostasis of the neural
microenvironment, particularly the deregulation of exist-
ing signaling networks that maintain the integrity of
myelin sheaths in mature Schwann cells, may be respon-
sible for rapid demyelination.
Although such early demyelination may not be sufficient
to exert a clinical manifestation of the disease, the under-
lying molecular basis may provide information for devel-
oping early diagnostic and therapeutic intervention
before the disease is aggravated by immune attack.
Role of M. leprae cell wall components and
Schwann cell receptors
As the binding of M. leprae and M. leprae cell wall
components to myelinated Schwann cell axon units is
sufficient to induce demyelination, the possibility exists
that receptors in myelinated Schwann cells that are asso-
ciated with M. leprae interactions may play a role in
perturbation of the homeostasis of the neural microenvir-
onment. Recent studies have shown a mechanism by
which M. leprae interacts with myelinated Schwann cells;
two of the most important M. leprae cell-wall-associated
Current Opinion in Immunology 2004, 16:511–518
molecules, phenolic glycolipid-1 (PGL-1; [13]) and ML-
LBP21 (for M. leprae laminin-binding 21 kDa protein;
[14]) have been identified as key bacterial molecules.
The corresponding key host molecules are the Schwann
cell basal laminae component laminin-2 [15] and its
receptors dystroglycan [16] and b4 integrin [15]. Consis-
tent with the capacity of the M. leprae cell-wall fraction to
induce demyelination, it was shown that PGL-1 in pur-
ified form could also induce demyelination as effectively
as the whole cell wall fraction [12]. Because PGL-1
interacts with the globular (G) domain of laminin-2,
particularly the G4-5 region, which is known to bind to
a-dystroglycan [17], it is possible that activation of signal-
ing in myelinated Schwann cells by M. leprae or PGL-1 via
the laminin-2-dystroglycan pathway may contribute to
the breakdown of the myelin sheath as a result of dereg-
ulation of the signaling network that maintains the
mature myelin sheaths.
Role of laminin-2 and its receptors in
myelination and demyelination
In myelinated nerve fibers, laminin-2 is the major com-
ponent of the basal lamina/extracellular matrix, which
deposits just outside Schwann cell membrane (see
Figure 1). During development, Schwann cells myelinate
axons in the continuous presence of basal lamina [3,18].
In order for the Schwann cell to respond to axonal signals
to initiate myelination, the Schwann cell must synthesize
extracellular matrix molecules (mainly the laminin-2 iso-
form and type IV collagen) and assemble them into the
basal lamina [18–20]. Under conditions in which the basal
lamina fails to assemble, Schwann cells are unable to
myelinate normally [18]. The genetic evidence for the
role of laminin-2 in myelination is based on the studies of
dystrophic mice and humans with congenital muscular
dystrophy (CMD); both have mutations in the laminin-a2
gene and are characterized by defects in Schwann-cell
myelination [21].
Laminin-2 in the basal lamina anchors to Schwann cells
via laminin-2 receptors, such as a6b1 integrin, a6b4
integrin and dystroglycan [22,23]. Despite the known
role of laminin-2 in myelination, the mechanism of
action of laminin-2 and the role of laminin-2 receptors
in myelination are largely unknown. Findings by Feltri
et al. [24] provide important insights into the role of
laminin-2 receptor b1 integrin in the differentiation of
myelinating Schwann cells. If the b1 integrin gene is
conditionally deleted in immature Schwann cells, the
myelination process is markedly delayed and even-
tually leads to the development of progressive neuro-
pathy [24]. Although there is no evidence for the
interaction of M. leprae with b1 integrin, M. leprae
may interfere with existing crosstalk between the lami-
nin receptors (or non-laminin receptors) responsible for
maintaining the mature myelin sheaths and mediating
cell signaling.
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 M. leprae-induced demyelination Rambukkana 513

Figure 1

M. leprae M. leprae
(a) (b)
Nucleus

Receptors
Axons Myelin
Axon sheath

Laminin-2
Basal lamina

Non-myelinated Schwann cell Myelinated Schwann cell

M. leprae
M. leprae Resist
invasion M. leprae
invasion

(c) Multiplication (d)

and release -Demyelination
-Axonal damage
(Nerve injury responses)
Proliferation
Re-infection

Proliferation
Innate and adaptive
Generate more immune responses
Schwann cells

Nerve regeneration

Bacterial survival

Nerve degeneration

Current Opinion in Immunology

Mycobacterium leprae-induced early demyelination and nerve injury response as both a bacterial strategy for intracellular survival and a
trigger for initiating immune-mediated response and injury. Upon PNS infection, M. leprae attaches to both (a) non-myelinated and (b)
myelinated Schwann cells, but preferentially invades the non-myelinated phenotype, where it multiplies, releases and re-infects more
non-myelinated Schwann cells. M. leprae attachment to myelinated Schwann cells is sufficient to induce demyelination and axonal damage.
To continue the intracellular life cycle within its preferred niche and to establish persistent infection, M. leprae generates increasing numbers
of non-myelinated Schwann cells both (c) directly by inducing proliferation of non-myelinated Schwann cells, and (d) indirectly by causing nerve
injury, demyelination and axonal damage, which normally induces Schwann cell proliferation to repair the damaged nerve (nerve regeneration).
Early nerve injury might also cause the destabilization of the neural microenvironment, leading to a cascade of other cellular responses that
eventually recruit the immune cells of the innate and adaptive immune systems, causing lasting damage to peripheral nerves.

Role of dystroglycan in myelination and
demyelination
An important non-integrin laminin-2 receptor in Schwann
cells is dystroglycan, which is encoded by a single gene
and cleaved into two proteins, a- and b-dystroglycan
[23,25]. Recent studies have shown that a-dystroglycan
is a Schwann cell receptor for non-lytic neurotrophic
pathogens, such as M. leprae and lymphocytic choriome-
ningitis virus (LCMV), and Lassa fever virus of the
arenavirus family [16,26
,27]. Dystroglycan thought to
be involved in the initiation of myelination, as dystrogly-
can is overexpressed with laminin-2 during peripheral

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514 Host–pathogen interactions
nerve myelination in postnatal rats [28], and its expression
is regulated in parallel with laminin-2 throughout the
degeneration process after nerve crush injury [29].
Furthermore, recent studies have shown that leprosy
bacillus and its component PGL-1 [30], which bind to
dystroglycan on Schwann cells through the G domain of
laminin-2 [13], cause demyelination [12].
Direct genetic evidence for the involvement of dystro-
glycan in peripheral nerve function has recently been
demonstrated by Saito et al. [31
] who showed that
selective deletion of Schwann cell dystroglycan (null
P0 mice lacking dystroglycan) results in severe neurolog-
ical dysfunction and a broad spectrum of morphological
abnormalities in myelination and nodal architecture, lead-
ing to defects in nerve conduction. Importantly, these
mice have dispersed distribution of sodium ion channels
on the node of Ranvier, suggesting that disruption of the
laminin–dystroglycan interaction is crucial not only for
peripheral nerve myelination but also for the functions of
ion channels at the nodes of myelinated axons [31
].
However, mechanisms by which dystroglycan regulates
the myelination process and ion-channel expression is
unknown. As M. leprae interacts with Schwann cells via
dystroglycan and laminin-2, and dystroglycan is involved
in signal transduction and myelination [25], signaling
through dystroglycan is likely to play a key role in
M. leprae-induced demyelination and axonal degeneration
during the early phase of infection.
Similar to M. leprae, LCMV uses dystroglycan as a recep-
tor for viral entry [27], but does not interact with laminin-
2 for Schwann-cell interactions [26
]. Unlike M. leprae,
LCMV infection does not cause any apparent effect on
mature myelinating Schwann cells [12,26
]. However,
persistent infection of immature Schwann cells rendered
these cells defective or incapable of forming a myelin
sheath when they differentiate into a myelinating phe-
notype in an in vitro differentiation model of Schwann
cells [26
]. Defects in myelination coincide with the
downregulation of dystroglycan protein expression and
disruption of the assembly of the laminin-2 network and
basal lamina on Schwann cell axon units. In addition,
infected Schwann cells that form mature myelin sheaths
undergo demyelination. These results further underscore
the role of the laminin–dystroglcan linkage in myelina-
tion and demyelination processes, and show the potential
use of LCMV as a model to dissect the molecular basis of
myelination.
Role of the dystroglycan–DRP2–periaxin
complex in myelination and demyelination
In myelinating Schwann cells, dystroglycan forms a com-
plex with dystroglycan-related protein 2 (DRP2) and
periaxin [32,33]. DRP2 is highly enriched in Schwann
cells and is specifically localized to the cytoplasm that
directly opposes the myelin sheath [33]. Periaxin, which
Current Opinion in Immunology 2004, 16:511–518
contains two PDZ domains and is implicated in the
assembly of macromolecular signaling complexes, how-
ever, is exquisitely Schwann-cell specific, and is concen-
trated to the abaxonal plasma membrane in the mature
myelin sheath [33]. Periaxin is essential for the stability of
myelin sheaths, as mice and humans lacking periaxin
develop a demyelinating peripheral neuropathy, which
manifests as a mixture of hypermyelination and demye-
lination [33]. The late onset of demyelination in periaxin-
null mice suggests that the dystroglycan–DRP2–periaxin
complex has a role in maintaining the myelin sheath,
possibly via signal transduction [33,34].
Because contact with the basal lamina modulates the
expression of genes required for myelination, laminin-2
receptors and associated molecules have been implicated
in mediating the responsiveness of Schwann cells to
extracellular signals from laminin-2 [35,36]. Such signals
could be induced by M. leprae upon attachment to lami-
nin-2 in the basal lamina. Periaxin binds DRP2 and
dimerizes at its PDZ domain, which probably contributes
to the distinctive clustering of the complex in the myelin-
forming Schwann-cell membrane [33]. Therefore, signal-
ing through the dystroglycan–DRP2–periaxin complex
may regulate the maintenance of the myelin sheath
during myelination, and M. leprae binding to laminin-2
may profoundly affect signaling mediated through the
dystroglycan–DRP2–periaxin complex, thereby promot-
ing breakdown of the myelin sheaths. As M. leprae appears
to use multiple strategies to subvert Schwann cell func-
tions [37], one cannot exclude the possibility of involve-
ment of other non-laminin receptors in M. leprae
interactions with myelinated Schwann cells, and signaling
mediated through such receptors could also be respon-
sible in mediating demyelination.
Early demyelination/nerve injury response as
a bacterial survival strategy
Non-myelinating Schwann cells as preferential targets
for M. leprae invasion
In the PNS, Schwann cells exist in two phenotypes,
myelinating Schwann cells that form one-to-one relation-
ships with large caliber axons and non-myelinating
Schwann cells that ensheath multiple small axons
(Figure 1; [3]). The former propagates rapid nerve con-
duction due to the larger caliber axon and the myelin
sheath, whereas the latter is mostly comprises smaller
sensory axons and provides slow nerve conduction.
Recent studies have shown that myelinated and non-
myelinated Schwann cells show distinct functional
responses to M. leprae infection. Although M. leprae binds
to both myelinated and non-myelinated Schwann cell-
axon units (Figure 1; [15]), it is the non-myelinated
Schwann cells that are susceptible to M. leprae invasion
and preferentially harbor M. leprae in the PNS [12].
Therefore, non-myelinating Schwann cells are not only
the natural host for the multiplication of M. leprae but also
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 M. leprae-induced demyelination Rambukkana 515

protect the organism from host immune responses Figure 2

[7,8,12,37,38]. For this reason, non-myelinating Schwann
cell resident M. leprae is a primary source of infection that (a)
not only causes nerve injury but is also responsible for the
continuous leakage of M. leprae and its antigens into the M
neural tissue milieu and circulation, and thus may lead to
a state of persistent infection or relapse (Figure 1; [8,38]). Ax
Myelinated Schwann cells, however, are extremely resis-
tant to M. leprae invasion but undergo demyelination and
axonal damage upon attachment to Schwann cell axon
units. In vivo induction of demyelination in lymphocyte-
deficient Rag-1/ mice [12] is also caused by similar
mechanism, as M. leprae fails to invade Schwann cells in
mice in general, but instead induces immune-mediated
demyelination in wild-type mice as a late event [39]. The
resistance of myelinated Schwann cells to M. leprae inva-
sion in in vitro cultures may be due to the compact myelin
sheath that physically occupies almost the entire cyto- (b)
plasm of this phenotype (Figure 2a). Interestingly, early
histopathological studies of nerve biopsies from leproma- M
tous leprosy (LL) patients have also shown that intracel- Ax
lular M. leprae is frequently seen in non-myelinated
Schwann cells in the early stage, but bacilli are rarely
seen in myelinating Schwann cells even in advanced LL
patients with high bacterial load [40]. These data rein-
force recent in vitro finding that demyelination during
early infection, before the immune response comes into
play, may be caused solely by the interaction of M. leprae
or its products with myelinating Schwann cells.

Nerve injury response as means of propagating

Schwann cells/intracellular niche
The cellular preference of the non-myelinating pheno-
type may provide M. leprae with a clear advantage for its
intracellular survival within the PNS. Because M. leprae
induces both demyelination and axonal damage in vitro,
this condition is somewhat similar to peripheral nerve
injury in vivo, where Schwann cells rapidly proliferate and
enclose the injured axons, an important event for the
promotion of nerve regeneration [41]. Strikingly,
Schwann cells proliferate significantly in M. leprae-treated
nerve tissue cultures with substantial demyelination and
axonal damage [12]. Such a neural microenvironment
created by early M. leprae infection may contribute to
Schwann cell proliferation. Therefore, it is likely that,
once invaded, M. leprae multiply as long as non-myelinat-
ing Schwann cells can tolerate the bacterial load (due to
the lack of anti-microbicidal machinery in Schwann cells)
and then release and invade more non-myelinating
Schwann cells or bind myelinated Schwann cells that sub-
sequently induce nerve degeneration (Figure 1). Be-
cause M. leprae is an obligate intracellular bacterium —
it must invade its preferred non-myelinating phenotype
for survival. However, as the infection progresses and
bacteria undergo unrestrained multiplication, the avail-
ability of non-myelinating Schwann cells becomes a limit-
ing factor. To avoid such a situation, leprosy bacilli must
Current Opinion in Immunology
Early in vivo demyelination induced by Mycobacterium leprae cell
wall in the absence of an adaptive immune response. The electron
micrographs are representative of sciatic nerves from Rag-1/ mice,
which lack T and B cells, 72 hours after intraneural administration of
(a) phosphate-buffered saline and (b) M. leprae cell wall.
Demyelinated and myelinated Schwann-cell axon units are shown by
the arrows and arrowheads, respectively. Ax, axon; M, myelin sheath.
generate more Schwann cells to secure it’s intracellular
niche. Recent studies provide evidence that M. leprae
generate increasing number of Schwann cells for long-
term intracellular survival by inducing nerve injury in
myelinated Schwann cells so that newly formed Schwann
cells (which usually lack myelin sheath) can be further
infected by released bacteria (Figure 1). It appears that
M. leprae takes full advantage of the property of peripheral
nerve injury response to propagate the bacterial reservoir.
Interestingly, more recent data show that the M. leprae
that reside inside Schwann cells can also induce cell
proliferation (N Tapinos and A Rambukkana, unpub-
lished). This provides an alternative strategy for pro-
pagating the intracellular niche for bacterial survival
(Figure 1). By inducing demyelination and axonal

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516 Host–pathogen interactions
damage in myelinating Schwann cells from the outside,
and by directing the proliferation of non-myelinating
Schwann cells from inside the cells, M. leprae seems to
have evolved to propagate its preferred niche for long-
term intracellular survival.
Is early demyelination a trigger for
immune-mediated responses?
Although nerve degeneration in the early phase of
M. leprae infection both in vitro and in vivo does not
involve immune cells, such nerve injury is likely to cause
the destabilization of the neural microenvironment. This
might subsequently lead to a cascade of other cellular
responses that eventually recruit immune cells, particu-
larly the cells of the innate immune system. Evidence
from studies with Rag-1/ knockout mice, which lack
mature B and T cells, and are thus unable to mount
adaptive immune response, showed the induction of
significant demyelination in sciatic nerves three days after
intraneural administration of M. leprae and its cell-wall
fraction (Figure 2; [12]). Although such early demyelina-
tion in Rag-1/ mice is mediated in the absence of B and
T cells, more recent studies provide evidence that the
components of the innate immune response come into
play during the late events of the infectious process
(N Tapinos and A Rambukkana, unpublished).
One of the families of pattern-recognition receptors of the
innate immune system is the Toll-like receptor (TLR)
family, which have been implicated in the initiation of
CD4þ T-cell responses [42]. Recent studies have identi-
fied the expression of TLRs in human leprosy skin
lesions, and it has been suggested that regulated expres-
sion and activation of TLRs at the site of disease con-
tribute to host defense against M. leprae [43
]. More
recently, Oliveira et al. [44] have shown the expression
of TLR2 receptors on human Schwann cells. As TLRs are
known to activate adaptive immune responses [42], it is
possible that TLRs contribute to the development of
initial neurological injury in vivo following non-immune-
mediated demyelination and axonal damage.
When cells of the innate immune response are at the site
of lesion, they recognize and respond to M. leprae, and
then activate adaptive immune responses by releasing
inflammatory mediators that mobilize neutrophils and
macrophages. As neutrophils, macrophages and pro-
inflammatory cytokines have been implicated in demye-
linating diseases [45], it is likely that the sequential
recruitment and propagation of immune cell populations,
preceded by non-immune-mediated demyelination and
axonal damage at the site of infection, could eventually
cause further aggravation of neurological injury during the
course of an M. leprae infection.
It should be emphasized that, although non-immune-
mediated mechanisms might play a role in the early phase
Current Opinion in Immunology 2004, 16:511–518
of neurological injury and initiation of the disease process,
it is the immune-mediated nerve damage that eventually
manifests clinically [8]. One of the earliest clinical symp-
toms of leprosy is the sensory loss, which is thought to be
caused by immune-mediated responses against M. leprae
antigens released from infected Schwann cells. Sensory
axons are mostly enclosed by non-myelinating Schwann
cells, in which M. leprae preferentially reside for long
periods of time. When M. leprae and M. leprae antigens are
released from such non-myelinating Schwann cells, both
non-myelinating and myelinating Schwann cells are
subjected to immune attack by infiltrating macrophages,
T cells and the cytokines released from these inflamma-
tory cells [7,8]. The outcome of such inflammatory
responses is the destruction of both Schwann cell phe-
notypes (comprising functional peripheral nerves) and
subsequent sensorimotor loss. Studies with cultured
human Schwann cells have shown this possibility, as
Schwann cells process and present M. leprae, as well as
recombinant proteins and peptides to MHC-class-II-
restricted CD4þ T cells, and are efficiently killed by
these activated T cells [46]. These findings provide
experimental evidence for a potential immune-mediated
mechanism of nerve damage in leprosy.
Conclusions
Nerve damage, the hallmark of M. leprae infection,
appears to occur during all stages of infection, although
early neurological abnormalities are not clinically detect-
able. Recent data suggest that early demyelination pro-
vides M. leprae with a survival advantage and possibly
aids the progression of infection, as demyelination and
subsequent axonal degeneration induce Schwann cell
proliferation, which, in turn, creates abundant non-
myelinating-type Schwann cells for M. leprae invasion,
bacterial replication and subsequent disease progression.
Understanding the different phases of M. leprae-induced
neurodegeneration, in which non-immune, innate
immune and adaptive immune responses play key roles,
should provide the rational for developing therapeutic
interventions not only for leprosy but also for demyeli-
nating neurodegenerative diseases in general. Therefore,
future studies should be directed towards delineating the
cellular and molecular basis of the different phases of
demyelination and axonal damage during M. leprae infec-
tion. Importantly, elucidating the molecular basis of
strategies that M. leprae utilize to survive and establish
a productive infection within the PNS will provide new
insights into the basic biology of glial cells.
Acknowledgements
I thank all of our collaborators and the members of my laboratory for
their contribution to the original published work, from which this review
was made possible. The studies cited from the author’s laboratory were
supported by World Health Organization and RO1 grants AI45816 and
NS45187 from the National Institute of Allergy and Infectious Diseases
(NIAID) and The National Institute of Neurological Disorders and
Stroke (NINDS).
www.sciencedirect.com

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