Update

TRENDS in Pharmacological Sciences

Vol.28 No.3

Research Focus

Treating leprosy: an Erb-al remedy?

Luke A. Noon and Alison C. Lloyd
MRC Laboratory for Molecular Cell Biology and the Department of Biochemistry, University College London, Gower Street, London
WC1E 6BT, UK

The leprosy pathogen Mycobacterium leprae attacks

Schwann cells in the peripheral nervous system, causing
them to demyelinate. Recent work by Tapinos et al.
shows that a direct mechanism of demyelination induced
by M. leprae depends on the binding of the bacterium to
the receptor tyrosine kinase ErbB2 on Schwann cells and
the resulting activation of the RasRafMEKERK pathway. These findings have relevance for the potential
treatment of leprosy and they highlight parallels between
the dedifferentiation signal in leprosy and that in nerve
injury and cancer.

Introduction
Despite a World Health Organization (http://www.who.int/
en/) resolution to eliminate leprosy by 2000, this disorder
remains a prevalent disease with up to 500 000 new cases
reported annually [1]. Leprosy is a chronic neurodegenerative disease that is caused by the obligate intracellular
pathogen Mycobacterium leprae. Much of the nerve
damage caused by the infection is the result of M. leprae
triggering extensive demyelination of Schwann cells (see
Glossary) in peripheral nerves. Recent evidence indicates
that the demyelination in the early stages of the infection
could be caused directly by the pathogen, rather than by an
immunological response to it, because the binding of M.
leprae to the surface of myelinating Schwann cells in
culture causes the cells to demyelinate [2,3]. In contrast
to the myelinating glia of the CNS (oligodendrocytes),
Schwann cells, in a highly coordinated response to nerve
injury, dedifferentiate, proliferate and then redifferentiate
to myelinate regrown axons. In this regard, Schwann cells
can be thought of as a regenerative cell-type that, upon
stimulation by appropriate damage signals, can provide
new cells for the repair process. Previous work has shown
that RasRafMEKERK signalling is sufficient to drive
the dedifferentiation of Schwann cells and seems to be the
pathway responsible for the dedifferentiation process following nerve injury [4]. However, the nature of the extracellular signal that is responsible for inducing the
dedifferentiation is controversial, with conflicting reports
as to whether neuregulin(s) is involved [5,6].
ErbB2: cellular target for Mycobacterium leprae
Tapinos et al. found that the dedifferentiation of Schwann
cells induced by M. leprae also requires signalling through
the RasRafMEKERK pathway [7] (Figure 1a). Importantly, they showed how the binding of the bacterium to the
Corresponding author: Lloyd, A.C. (alison.lloyd@ucl.ac.uk).
Available online 2 February 2007.
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surface of a Schwann cell activates this signalling cascade,

which is commonly activated by receptor tyrosine kinases.
Looking for cell surface proteins that had been tyrosine
phosphorylated following M. leprae exposure, the authors
identified the ErbB2 receptor and showed, in a series of
convincing experiments, that it is the receptor for M. leprae
on Schwann cells and that it is activated by the binding of
the bacterium.
In what has been coined deaf and dumb signalling [8],
ErbB2ErbB3 receptor heterodimerization is typically
required for signalling in Schwann cells in response to
binding of the neuregulin family of ligands. The ErbB2
receptor cannot bind to ligand (deaf) and, therefore,
requires heterodimerization with a ligand-binding ErbB
family member in the case of Schwann cells, this is the
ErbB3 receptor, which lacks intrinsic tyrosine kinase
activity (dumb). It has, however, been reported that
ErbB2 can homodimerize and, thereby, signal on its
own, in the absence of ligand, if the receptor is overexpressed as is the case in many types of epithelial cancer
[9]. Heterologous expression studies showed that ErbB2
alone is sufficient to bind to M. leprae. Importantly, small
interfering (si)RNA experiments then showed that M.
leprae-induced ERK activation, unlike signalling induced
by the ligand neuregulin, occurs independently of ErbB3.
These results indicate that, in Schwann cells (which
express only ErbB2 and ErbB3), M. leprae-induced ErbB2
activation could result from homodimerization of this
receptor, and thus might be analogous to ErbB2 signalling
in cancer cells.
Mycobacterium leprae drives demyelination by
activating ERK
Various pharmacological agents have been crucial for
investigating the signalling pathways that are activated
by M. leprae and are potential therapeutics for both leprosy
and other demyelinating neuropathies. In the study by
Tapinos et al. [7], Herceptin1, which is a humanized
monoclonal ErbB2 antibody that is used in the treatment
of breast cancer, blocked the binding of M. leprae to the
receptor and, therefore, prevented ERK activation in
human Schwann cells (Figure 1). Furthermore, the
Glossary
Neuregulin: a family of membrane-bound and secreted growth and differentiation factors that activates the ErbB family of receptors. In Schwann cells,
neuregulins function through ErbB2ErbB3 heterodimers and have crucial
roles in regulating Schwann cell proliferation, differentiation and survival.
Oligodendrocytes: myelinating glial cells of the CNS.
Schwann cells: myelinating glial cells of the peripheral nervous system.

0165-6147/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.01.004

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TRENDS in Pharmacological Sciences

ErbB1ErbB2 tyrosine kinase inhibitor PKI166 blocked

M. leprae-induced demyelination in both an in vitro assay
and a mouse model system. Interestingly, PKI166 has also
been reported to inhibit Schwann cell demyelination following nerve injury, indicating that Schwann cells might
also use ErbB receptors to sense axonal damage [5]. However, these findings remain controversial because other
reports claim that ErbB2 signalling is not involved in the
Schwann cell response to nerve injury [6]. What is clear,
however, is that neuregulin can drive Schwann cell dedifferentiation in in vitro myelination assays, presumably
through ErbB2ErbB3 signalling [5,10]. Therefore, the
latest findings by Tapinos et al. indicate that M. leprae
could subvert a pre-existing dedifferentiation signal by
activating ErbB2 to short-circuit the normal requirement
for ligand-induced ErbB2ErbB3 heterodimerization. In a
further link to the pathology of Schwann cells, the authors
demonstrate that this dedifferentiation pathway requires
Ras recruitment by son of sevenless (SOS) to activate
MEKERK signalling. Ras activation has been linked to
tumour formation in Schwann cells in patients with neurofibromatosis type 1, who lack the RasGAP neurofibromin, and the RasRafMEKERK pathway can drive
dedifferentiation [11]. Therefore, both cancer formation
and M. leprae infection might hijack a common signalling
pathway to drive differentiated Schwann cells to a more
proliferative state.
Propagating the infection
So, M. leprae can bind to myelinated Schwann cells through
the ErbB2 receptor and drive the cells to dedifferentiate by
activating RasRafMEKERK signalling. Once the Schwann cells have dedifferentiated, M. leprae can invade them
and proliferate within them [12]. Healthy axons in adult
nerves are ensheathed not only by myelinating Schwann

Vol.28 No.3

cells but also by specialized non-myelinating Schwann cells,

and M. leprae can also invade these latter cells. Thus, both
dedifferentiated and non-myelinating Schwann cells can
function as a reservoir for infection. Interestingly, in a
previous publication, Tapinos and Rambukkana showed
that M. leprae can drive the proliferation of dedifferentiated
Schwann cells, presumably as a means to increase the size of
the host reservoir [12]. Intriguingly, this proliferative signal
also requires ERK but, in this case, activation occurs by a
different signalling pathway that seems to involve protein
kinase C (PKC)e and the non-receptor tyrosine kinase Lck
(Figure 1b). A normal Schwann cell also uses the ERK
signalling pathway following injury both to dedifferentiate
and to proliferate. Because ERK levels drop during the
repair process, Schwann cells can redifferentiate and remyelinate the regenerated axons. M. leprae seems to have
succeeded in subverting both of these processes: it binds
to the ErbB2 receptor, activating ERK signalling, which
then drives the dedifferentiation of myelinating Schwann
cells so that the bacterium can invade. Once inside, M. leprae
replicates and forces the host cell to replicate by activating
ERK signalling through the PKCLck pathway (Figure 1b).
Presumably, this amplifies the infection, releasing more
bacteria, which would provoke further demyelination and
immune-cell recruitment, thus increasing the damage.
Moreover, because constitutive ERK signalling can block
remyelination [4], the ability to remyelinate is likely to be
curtailed in infected Schwann cells.
Costs and benefits?
A more difficult issue is whether this new understanding of
how M. leprae disrupts normal Schwann cell behaviour
has implications for therapy. The current treatment protocols for leprosy patients involve long-term treatment
with multiple antibiotics [1]. Whereas eradication of

Figure 1. Mycobacterium leprae binds to the ErbB2 receptor to induce Schwann cell demyelination and proliferation. (a) The binding of M. leprae (ML) to ErbB2 on the
surface of myelinated Schwann cells triggers demyelination through the RasRafMEKERK pathway. Inhibitors such as Herceptin1, PKI166 and U0126 block activation of
this pathway in response to M. leprae contact. (b) Intracellular M. leprae induces proliferation of non-myelinated Schwann cells through a different route to ERK that
involves PKCe and LCK and that is independent of signalling through the RasRafMEK pathway.
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Update

TRENDS in Pharmacological Sciences

the pathogen is likely to remain the ideal and most

cost-efficient regimen, it might also be beneficial to add
a drug that can block the early pathogen-induced demyelination, such as Herceptin1, PKI166 or other ErbB2
inhibitors. Moreover, it seems that ERK signalling in
infected dedifferentiated cells increases the size of the
reservoir and is likely to block remyelination. Because
ERK activation by the intracellular pathogen is the result
of PKCeLck signalling to ERK, different inhibitors would
be required to inhibit this process but might act on a double
front both to limit the spread of the disease and to enable
repair to take place. However, these are still early days.
More research is required to understand fully how M.
leprae disrupts normal Schwann cell behaviour and to
assess the overall benefits and costs of therapeutics to
what seem to be promising new targets for the treatment
of this disease.
Acknowledgements
A.C.L. is a Cancer Research UK (CRUK) Senior Cancer Research Fellow
and L.A.N. is funded by a CRUK programme grant. We thank Martin
Raff and members of the Lloyd laboratory for helpful comments.

References
1 Lockwood, D.N. and Suneetha, S. (2005) Leprosy: too complex a disease
for a simple elimination paradigm. Bull. World Health Organ. 83, 230
235

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2 Rambukkana, A. et al. (2002) Contact-dependent demyelination by

Mycobacterium leprae in the absence of immune cells. Science 296,
927931
3 Rambukkana, A. (2004) Mycobacterium leprae-induced demyelination:
a model for early nerve degeneration. Curr. Opin. Immunol. 16, 511
518
4 Harrisingh, M.C. et al. (2004) The Ras/Raf/ERK signalling
pathway drives Schwann cell dedifferentiation. EMBO J. 23, 3061
3071
5 Guertin, A.D. et al. (2005) Microanatomy of axon/glial signaling during
Wallerian degeneration. J. Neurosci. 25, 34783487
6 Atanasoski, S. et al. (2006) ErbB2 signaling in Schwann cells is mostly
dispensable for maintenance of myelinated peripheral nerves and
proliferation of adult Schwann cells after injury. J. Neurosci. 26,
21242131
7 Tapinos, N. et al. (2006) ErbB2 receptor tyrosine kinase signaling
mediates early demyelination induced by leprosy bacilli. Nat. Med.
12, 961966
8 Citri, A. et al. (2003) The deaf and the dumb: the biology of ErbB-2 and
ErbB-3. Exp. Cell Res. 284, 5465
9 Burgess, A.W. et al. (2003) An open-and-shut case? Recent insights into
the activation of EGF/ErbB receptors. Mol. Cell 12, 541552
10 Zanazzi, G. et al. (2001) Glial growth factor/neuregulin inhibits
Schwann cell myelination and induces demyelination. J. Cell Biol.
152, 12891299
11 Harrisingh, M.C. and Lloyd, A.C. (2004) Ras/Raf/ERK signalling and
NF1. Cell Cycle 3, 12551258
12 Tapinos, N. and Rambukkana, A. (2005) Insights into regulation of
human Schwann cell proliferation by Erk1/2 via a MEK-independent
and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad.
Sci. U. S. A. 102, 91889193

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