Contact-Dependent Demyelination by Mycobacterium leprae in the Absence of Immune Cells

Abstract

Demyelination results in severe disability in many neurodegenerative diseases and nervous system infections, and it is typically mediated by inflammatory responses. Mycobacterium leprae, the causative organism of leprosy, induced rapid demyelination by a contact-dependent mechanism in the absence of immune cells in an in vitro nerve tissue culture model and in Rag1-knockout (Rag1-/-) mice, which lack mature B and T lymphocytes. Myelinated Schwann cells were resistant to M. leprae invasion but undergo demyelination upon bacterial attachment, whereas nonmyelinated Schwann cells harbor intracellular M. leprae in large numbers. During M. leprae-induced demyelination, Schwann cells proliferate significantly both in vitro and in vivo and generate a more nonmyelinated phenotype, thereby securing the intracellular niche for M. leprae.

Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli

“…Schwann cells serve as a reservoir for M. leprae after peripheral nervous system infection (7,8,10,11). To recapitulate the fate of human Schwann cells in response to long-term intracellular residence of M. leprae in vivo, we isolated adult Schwann cells from peripheral nerves from different human donors, and each isolate was purified to homogeneity by FACS sorting using mAbs against neurotrophin receptor p75 as a marker for Schwann cells (18), and further characterized (Fig.…”

“…We have shown that myelinating and nonmyelinating Schwann cells display distinct functional responses to infection with Mycobacterium leprae, the causative organism of leprosy, and cell proliferation is a common feature during infection (7)(8)(9). Subsequent to infection, M. leprae preferentially invade human nonmyelinating Schwann cells and maintain long-term intracellular bacterial survival, which eventually leads to irreversible immune-mediated peripheral nerve damage, the hallmark of leprosy (10)(11)(12)(13)(14).…”

“…Subsequent to infection, M. leprae preferentially invade human nonmyelinating Schwann cells and maintain long-term intracellular bacterial survival, which eventually leads to irreversible immune-mediated peripheral nerve damage, the hallmark of leprosy (10)(11)(12)(13)(14). One key to the pathogenic potential of M. leprae survival lies in the ability of this extremely slow-growing and strictly obligate intracellular bacterium to propagate its preferred niche so that sufficient Schwann cells are available for bacterial residence, survival, and replication (7,8,13). Using highly purified primary human Schwann cells, which mimic nonmyelinating phenotype-like Schwann cells, we found that M. leprae have the capacity to induce Schwann cell proliferation from inside the cells several weeks after infection.…”

Mycobacterial polyketide-associated proteins are acyltransferases: Proof of principle with Mycobacterium tuberculosis PapA5

“…These compounds include (phenol)phthiocerol (POL) and phthiodiolone (PONE) dimycocerosate esters (PDIMs) (2, 3) (Scheme 1, which is published as supporting information on the PNAS web site). Mycobacterium tuberculosis (Mt) mutants deficient in PDIM production are attenuated in mice, and PDIMs of Mycobacterium leprae (phenolic glycolipids or mycoside B) promote Schwann cell tropism (2)(3)(4).…”

Involvement of 9-O-Acetyl GD3 Ganglioside in Mycobacterium leprae Infection of Schwann Cells*

“…Phenolic glycolipid-I, a major unique glycoconjugate on the ML surface, binds laminin-2, which explains the predilection of the bacterium for peripheral nerves (4). In vitro and in vivo studies in Rag-1 Ϫ/Ϫ mice, which lack B and T lymphocytes, showed that ML attachment to the SC surface is sufficient to cause demyelination in peripheral nerves (5). This effect was found to be dependent on neuregulin receptor, ErbB-2, and ERK 1/2 activation by ML, leading to MAPK signaling and proliferation (6).…”