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Schwann cell invasion by M. Leprae: the probable Trojan horse.

The ability of Mycobacterium leprae to invade and sustain inside Schwann cells is vital in the pathogenesis of leprosy. M. leprae has the capacity to induce Schwann cell proliferation thereby providing enough host cells for bacterial propagation. It also has the ability to cause extensive demyelination of peripheral nerves, the cause for most of its dreaded sequelae. (1) Whether this demyelination is a direct effect of the pathogen or an immunological response to it is still debated (2) (Table 1).

Schwann cells unlike oligodendrocytes can dedifferentiate, proliferate and re-differentiate in response to Ras-Raf-MEK-ERK signalling following nerve injury. (3) Intracellular M. leprae can activate ERK directly by an MEK independent pathway. (4) But Extracellular M. leprae achieves this through the conventional Ras-Raf-MEK-ERK signalling through ErbB2, a distinctive receptor tyrosine kinase belonging to the epidermal growth factor receptor family. (5) That puts ErbB2 at the centre-stage of Schwann cell invasion as an important drug target. A monoclonal antibody against ErbB2 called Herceptin (trastuzumab) is already in use for breast cancer. (6)

ErbB2 is unique in its family since it has an open configuration and can form heterodimers with other members of the family even in the absence of a ligand. (7) ErbB2 can also homodimerise and initiate signalling if over expressed as in several epithelial carcinomas. Homodimerisation is the likely mechanism of signalling in M. leprae in the absence of ErbB2 over-expression. (5) However M. leprae has no known ligand(s) for ErbB2. (8) Hence some unknown ligand(s) from M. leprae causes downstream ERK signalling by facilitating homodimerisation even when normally expressed.

Members of the EGFR family have high and low affinity binding sites. The affinity of EGF for binding to the second site on an EGFR dimer is several times lower than the first site leading to receptor dimer disassembly. (9) However the dissociation of activated dimers supplies enough monomers for activation of unliganded receptors leading to local propagation of signalling stimulus. Since ErbB2 has high degree of sequence homology with other members of the EGFR family, (10) the unknown ligand(s) may be acting in the same way.

Since ErBB2 has strong structural similarity with other EGFRs, it is likely that the unknown ligand has some sequence similarity with the known ligands for EGFR family. A BLAST (11) search performed with human EGF against the non redundant (nr) mycobacterial protein database at the National Centre for Biotechnology Information (NCBI) (Table 2), showed a sequence similarity (Expect Value 0022) with a short segment of a putative multidrug resistance pump protein (NCBI RefSeq accession number NP_302390).

The Blast search was performed with BLOSUM 45 matrix as the sequence similarity, if any would be evolutionally divergent. (12) No EGF-like domains (PROSITE--PDOC00021) were found in M. leprae. Other known EGFR family ligands (13) like heregulin-[alpha] (HRG-[alpha]), heregulin-[beta] (HRG-[beta]), transforming growth factor--[alpha] (TGF-[alpha]), betacellulin (BC) and amphiregulin (AR) did not show any significant blast hits (Table 3).

A PSI-BLAST (14) performed with Multiple sequence alignment (MSA) prepared from these ligands against mycobacterial proteins to identify any conserved regions. However it did not yield any hits.

The segment which showed similarity was upstream from an ABC transporter (15) transmembrane domain (pfam 06472). Though the ABC transporter domain had homologues in several other mycobacteria, the upstream segment was not conserved and had more number of alanine and valine residues in M. leprae than other mycobacteria. A mutation (Ile655Va1) is known to stabilise the ErbB2 active dimeric state owing to substitution of the bulk side chain of Ile with a smaller one of Val leading to tighter packing of the Trans membrane region of ErbB2 dimer. (16,17) Whether this alanine and valine rich segment can influence ErbB2 dimer stability or induce lateral signalling by negative cooperativity with EGF remains to be seen.

Apparent lack of association between leprosy and malignancy is also unsettled considering the strong association of ErbB2 with several malignancies especially breast cancer. This may be related to the fact that ErbB2 is involved only in the initial invasion by M. leprae. Besides density of EGFR is important in negative cooperativity and lateral signalling. (9) The ErbB2 density of Schwann cells may be ideal for this phenomenon to occur.

A single BLAST search result is insufficient to incriminate this putative transporter protein as the cause of Schwann cell invasion by M. leprae. But its apparent proximity to an evolutionally important drug resistance domain and the fact that it has been added recently to the sequence database makes me wonder whether it is a Trojan horse.

References

(1) Franklin RJ, Zhao C. Tyrosine kinases: maiming myelin in leprosy. Nat Med, 2006; 12: 889-890.

(2) Rambukkana A. Mycobacterium leprae-induced demyelination: a model for early nerve degeneration. Curr Opin Immunol, 2004; 16: 511-518.

(3) Harrisingh MC, Perez-Nadales E, Parkinson DB et al. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. Embo J, 2004; 23: 3061-3071.

(4) Tapinos N, Rambukkana A. Insights into regulation of human Schwann cell proliferation by Erkl/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc Natl Acad Sci U S A, 2005; 102: 9188-9193.

(5) Noon LA, Lloyd AC. Treating leprosy: an Erb-al remedy? Trends Pharmacol Sci, 2007; 28: 103-105.

(6) Cho HS, Mason K, Ramyar KX et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature, 2003; 421(6924): 756-760.

(7) Tapinos N, Ohnishi M, Rambukkana A. ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli. Nat Med, 2006; 12: 961-966.

(8) Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Ear J Cancer, 2001; 37(Suppl 4): S3-S8.

(9) Macdonald JL, Pike LJ. Heterogeneity in EGF-binding affinities arises from negative cooperativity in an aggregating system. Proc Natl Acad Sci U S A, 2008; 105: 112-117.

(10) Bagossi P, Horvath G, Vereb G et al. Molecular modeling of nearly full-length ErbB2 receptor. Biophys J, 2005; 88: 1354-1363.

(11) Altschul SF, Gish W, Miller W et al. Basic local alignment search tool. J Mol Biol, 1990; 215: 403-410.

(12) Mihalek I, Res I, Lichtarge O. Background frequencies for residue variability estimates: BLOSUM revisited. BMC Bioinformatics, 2007; 8: 488.

(13) Pero SC, Shukla GS, Armstrong AL et al. Identification of a small peptide that inhibits the phosphorylation of ErbB2 and proliferation of ErbB2 overexpressing breast cancer cells. Int J Cancer, 2004; 111: 951-960.

(14) Altschul SF, Koonin EV. Iterated profile searches with PSI-BLAST-a tool for discovery in protein databases. Trends Biochem Sci, 1998; 23: 444-447.

(15) Kelly L, Karchin R, Sali A. Protein interactions and disease phenotypes in the ABC transporter superfamily. Pac Symp Biocomput, 2007; 51-63.

(16) Xie D, Shu XO, Deng Z et al. Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst, 2000; 92: 412-417.

(17) Bocharov EV, Mineev KS, Volynsky PE et al. Spatial structure of dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J Biol Chem, 2008; 6950-2956.

BELL RAJ EAPEN

Specialist Dermatologist, Kaya Skin Clinic, Dubai, United Arab Emirates

(e-mail: bell. eapen@dermatologist.co.in)
Table 1. Abbreviations used

ABC Transporter   ATP-binding cassette transporter
BLAST             Basic Local Alignment Search Tool
BLOSUM            BLOcks of Amino Acid Substitution Matrix
EGF               Epidermal growth factor
EGFR              Epidermal growth factor receptor
ErbB2             Member of the ErbB protein family. Also
                    known as HER2/Neu
ERK               Extracellular signal-regulated Kinases
Ile               amino acid isoleucine
MEK               Mitogen-activated protein kinase kinase
NCBI              National Center for Biotechnology Information
PSI-BLAST         Position-Specific Iterative BLAST
Val               amino acid Valine

Table 2. Results of BLAST search performed with human EGF against
the non redundant mycobacterial protein database at NCBI

Accession   Protein Name                                    E-Value
Number

NP_302390   Probable multidrug resistance pump               0.022
NP_301513   GTP-binding protein LepA                         0.40
NP_301554   Putative -alanyl-D-alanine carboxypeptidase      2.2
NP_302118   heat shock protein 90                            2.4
NP_302586   UDP-N-acetylenolpyruvoylglucosamine reductase    4.4
NP_301491   6-phosphogluconolactonase                        6.5
NP_301739   Possible ATP/GTP-binding protein                 7.8
NP_301890   Mycocerosic acid synthase                        8.8

Table 3. Accession numbers of ErbB2 ligands

Protein        Accession number

EGF            NP_001954
HRG-[alpha]    NP_039258
HRG-[beta]     NP_039250
TGF-[alpha]    NP_003227
Betacellulin   NP_001720
Amphiregulin   NP_001648
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Title Annotation:Mycobacterium leprae
Author:Eapen, Bell Raj
Publication:Leprosy Review
Article Type:Clinical report
Geographic Code:7UNIT
Date:Sep 1, 2008
Words:1371
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