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 tack 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.

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…Through this unconventional mechanism M leprae increased ERK1/2 phosphorylation and caused demyelination that could be inhibited by the ERK1/2 blocker U0126 (Rambukkana et al, 2002;Tapinos et al, 2006).…”

Cutaneous lesions sensory impairment recovery and nerve regeneration in leprosy patients

“…During the progression of the infection, M. leprae induces demyelination and axonal damage in order to provide a sufficient intracellular niche for bacterial survival (Rambukkana et al 2002). Tactile sensation, which is conducted by large myelinated axons, is affected later in the disease, which explains the reduced damage to this sensory modality -relative to nociception and thermosensation -that was observed in this sample.…”

“…M. leprae is harboured in both non-myelinating and myelinating Schwann cells, but because it is an obligate intracellular bacterium, it needs to invade unmyelinating cells to survive within the peripheral nervous system (Rambukkana et al 2002). As a result, small nerve fibers are easily affected.…”

“…This need accounts for the higher frequency of recovery of thermal and pain sensations that we observed compared to the recovery of tactile function. However, M. leprae-induced demyelination and axonal damage resemble peripheral nerve injuries in Wallerian degeneration, in which Schwann cells rapidly proliferate and promote the regeneration of injured nerves (Rambukkana et al 2002). a: sensation of monofilaments 1-4 (300-0.2g) was considered as hypoesthesia; b: calculated by grouping abolished and hypoesthesic into impaired for comparison with normal tactile sensation due to 0 values; NA: not available (no nerves were observed in the sections).…”

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

“…Increasing efforts over the past decade to understand important early events in the interaction of M. leprae with peripheral nerves have resulted in the characterization of bacterial adhesins and receptors involved in M. leprae attachment to Schwann cells (de Melo Marques et al 2000, Rambukkana 2004, Soares de Lima et al 2005. The effects of M. leprae on myelin sheath integrity (Rambukkana et al 2002, Tapinos et al 2006) and on Schwann cell proliferation (Tapinos & Rambukkana 2005) have been investigated as well.…”