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. Whether this demyelination is a direct effect of the pathogen or an immunological response to it is still debated (Table 1). Schwann cells unlike oligodendrocytes can dedifferentiate, proliferate and re-differentiate in response to Ras-Raf-MEK-ERK signalling following nerve injury. Intracellular M. leprae can activate ERK directly by an MEK independent pathway. 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. 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. 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. 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. However M. leprae has no known ligand(s) for ErbB2. 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. 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, 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 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 0·022) 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. No EGF-like domains (PROSITE – PDOC00021) were found in M. leprae. Other known EGFR family ligands like heregulin-a (HRG-a), heregulin-b (HRG-b), transforming growth factor – a (TGF-a), betacellulin (BC) and amphiregulin (AR) did not show any significant blast hits (Table 3). Lepr Rev (2008) 79, 335–337