Confocal microscopy shows that
M. leprae colocalizes with ErbB2
on Schwann cell membranes.
An old disease is showing researchers new tricks. Leprosy, also called Hansen disease, a bacterial infection that causes nerve damage and skin lesions, was first reported over 2500 years ago. Mycobacterium leprae (M. leprae) affects Schwann cells, which generate and maintain the myelin sheath coating peripheral nerves. Tapinos et al. report that M. leprae causes demyelination by binding to the growth factor receptor ErbB2 on Schwann cells, in a recent article in Nature Medicine.
The authors previously showed that demyelination associated with leprosy is not caused by the immune system. In the new paper, they identify the cell signaling pathway that is responsible. In rat and human Schwann cell–neuron cocultures, M. leprae induced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (Erk) 1/2 within 15 minutes of treatment. The MAPK pathway inhibitor U0126 prevented M. leprae-induced phosphorylation of Erk 1/2 and also prevented M. leprae-induced demyelination.
Growth factor receptors, many of which are receptor tyrosine kinases, activate the MAPK pathway. M. leprae increased tyrosine phosphorylation in Schwann cell membranes. The size of the phosphotyrosine-positive band in Schwann cell immunoblots suggested that ErbB2 might be the receptor tyrosine kinase activated by M. leprae. Schwann cells treated with M. leprae showed a 400% increase in tyrosine phosphorylation of ErbB2 and a 600% increase in phosphorylation of the ErbB2 residue that couples to MAPK signaling, relative to untreated Schwann cells. ErbB2 usually heterodimerizes with and phosphorylates ErbB3 after ErbB3 binds its ligand neuregulin 1. However, M. leprae treatment did not phosphorylate ErbB3, and ErbB3 knockdown did not prevent M. leprae-induced phosphorylation of ErbB2, suggesting that M. leprae signals through ErbB2 by an alternative mechanism.
ErbB2 turned out to be a receptor for M. leprae that couples to MAPK signaling. M. leprae colocalized with ErbB2 on the surface of Schwann cells and caused ErbB2 clustering, but neuregulin 1 did not. The extracellular portion of ErbB2 was sufficient to induce M. leprae binding, which was disrupted by Herceptin, a drug that contains ErbB2 antibodies. Herceptin also prevented the M. leprae-induced increase in Erk 1/2 in human Schwann cells.
The ErbB1–ErbB2 kinase inhibitor PKI 166 prevented M. leprae from demyelinating neurons cocultured with Schwann cells, which do not express ErbB1, suggesting that ErbB2 signaling mediates M. leprae-induced myelin damage. PKI 166 also reduced demyelination in mice injected with M. leprae. PKI 166 may therefore prove to be an important clinical tool not only for leprosy, which is successfully treated with antibiotics, but perhaps also for other demyelinating diseases, including Guillian-Barré disease and multiple sclerosis, which should now be tested to determine whether they also involve ErbB2 signaling.