Mycobacterium leprae is one of the renowned pathogens in Microbiology. Of-course, the big share of infection in the group goes to M tuberculosis. Leprae bacilli has not been studied in details compared to other pathogen. The most important hindrance is it has not been cultivable in Culture media (Maybe Culturomics will help in future). Till date, the pathogenesis of leprae bacilli has not been well understood. It was assumed that they somehow the pathogen beats the neuronal cells especially Schwann cells. The assumption isn't completely wrong but (as shown in the paper that am going talk about), not right either. The game changing paper has been difficult to digest, but its a huge leap. Let me start with some basics and then we move on to what the paper reveals.
|Photo 1: Leprae Bacilli. Source|
|Fig 1: Schwann cells. Source|
|Fig 2: Mycobacterium leprae binds to the ErbB2 receptor to induce Schwann cell demyelination and proliferation. Source|
So what we had known earlier? As I said, the M leprae was known to damage schwann cells. In fact that fits well with explanation. Much of the nerve damage caused by the infection is the result of M. leprae triggering extensive demyelination of schwann cells in peripheral nerves. This causes a loss of nerve conduction functions and leads to what is the classical numbness (Loss of sensation) in the disease. Looking into the details of demyelination, lead to the understanding that demyelination can be induced by a Ras- Raf pathway (Ras–Raf–MEK–ERK). The explanation is shown below in Fig 2.
The most common ultra-structural finding of infection, is infection of epineurial vascular and lymphatic endothelial cells. The receptor for schwann cell is the PGL-1 (Phenolic glycolipid-1) or LBP21 receptor on M. leprae which binds to the α-2 side chain of laminin-2 as well as the related α-dystroglycan receptor.The entry most probably is via complement receptor 3-mediated phagocytosis.
|Fig 3: A model for the binding interactions of individual α2LG modules of the G domain with PGL-1 and ML-LBP21 in the M. leprae cell wall. Source|
With this background, it is obvious that schwann cell has an important role to play in the pathogenesis of leprosy. But it is also unclear as to what happens.
|Fig 4: Schwann cell reprograming and implications. Source|
A second related paper by Wegner etal. has some more to say. SOX-10 is an essential determinant of Schwann cell identity and is the prime candidate to be inactivated that cause lineage de-differentiaition. On prolonged incubation of in mesenchymal stem cell medium the bacteria- containing stem like cells, become strongly proliferative and gains migratory properties. This possibly is the cause for pathogen dissemination.
What is so striking about this understanding is that after all shwann cells are not destroyed. Rather, they are converted into stem cell like lineage. The mechanism first of all provides me with something to think about as a model system for stem cell inducing properties, and also clarifies leprae molecular infection. Take home message is "Leprae bacilli is Schwann cell gene programmer".
Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, & Rambukkana A (2013). Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection. Cell, 152 (1-2), 51-67 PMID: 23332746
Wegner M (2013). Mighty bugs: leprosy bacteria turn schwann cells into stem cells. Cell, 152 (1-2), 15-6 PMID: 23332743
1. Luke A. Noon,Alison C. Lloyd. Treating leprosy: an Erb-al remedy.(2007). Trends in Pharmocological science. ; 28(3); 103–105. Link
2. Tabouret G, Astarie-Dequeker C, Demangel C, Malaga W, Constant P, et al. (2010) Mycobacterium leprae Phenolglycolipid-1 Expressed by Engineered M. bovis BCG Modulates Early Interaction with Human Phagocytes. PLoS Pathog 6(10): e1001159. Link