Mycobacterium leprae is unique among bacterial pathogens in its ability to invade the peripheral nervous system and to cause nerve damage, which accounts for the disabilities in leprosy patients. This property makes M. leprae a model to study the mechanism of nerve damage, particularly demyelination, in other neurodegenerative diseases. The components of M. leprae which bind peripheral nerves and induce nerve damage are not known. The PI proposes that M. leprae interferes with critical Schwann cell functions and subsequently causes nerve dysfunction before the immune response comes into play. Using a well-characterized in vitro Schwann cell-sensory neuron co-culture system, which mimics in vivo conditions, but is devoid of immune cells, the PI found that M. leprae and its cell wall fraction alone induce significant demyelination and axonal damage. The PI and colleagues have recently shown that laminin-2 is an initial neural target of M. leprae; since the laminin-2 isoform completely surrounds the Schwann cell-axon units, the PI proposes that M. leprae should bind to laminin-2 before inducing nerve damage in early infection. Therefore, laminin-2-binding antigens are the most likely components of M. leprae that mediate bacterial binding and invasion, and also induce nerve damage. The main theme of the application is to systematically identify the laminin-binding components of M. leprae that mediate the initial interaction with peripheral nerves and characterize their capacity to induce nerve damage. In preliminary studies, the PI has shown that phenolic glycolipid 1 (PGL-1) and a novel M. leprae cell wall protein of 21 kDa bind laminin-2. These data also suggest the presence of other laminin-binding components of M. leprae. Since the preliminary studies indicate that PGL-1 alone can induce significant demyelination, the PI proposes that the laminin-binding components are capable of inducing demyelination. Therefore, the PI proposes the following: (1) characterize the laminin-2-binding activity of PGL-1 and the 21 kDa protein and their roles in Schwann cell invasion, (2) identify and characterize other potential laminin-binding components in the M. leprae genome with special emphasis on M. leprae-specific proteins by screening an ordered cosmid library of M. leprae, using laminin-2 as a probe, and (3) characterize the demyelination and axonal damage induced by M. leprae laminin-binding components. These studies should provide important insights into the early molecular events of nerve damage in leprosy and other neurodegenerative diseases and will eventually lead to the development of novel therapeutics and diagnostics for peripheral neuropathies.
