Friday, February 15, 2013

Schwan cell programmer- Leprae

     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
    Mycobacterium leprae (Casually known as Hansen's Bacilli, causing Hansen's disease or Leprosy), is a member of Mycobacterium. The infection is considered as the major factor in crippling disease of infectious origin. Their elegance comes from the point that, they infect the nerves (Not other bacteria can do that, though there are viral examples!!!), and they infect only Peripheral nerves (Not the Central). The effected site ceases to show signs of sensation. The condition is basically active neuritis. Of all the cells that are effected by Leprae, Schwann cell involvement is distinct.

Fig 1: Schwann cells. Source
     Schwann cells or neurolemmocytes (named after physiologist Theodor Schwann), part of peripheral nerve structure. They are considered as equivalent to Oligodendrocytes present in the CNS. The function of Schwann cells is to produce a myelin sheath, and repair damaged neurons. Myelin sheath provides an insulation to nerve conduction. This arrangement helps in faster conduction of nerve impulses. This can be explained by the fact the nerve conduction is slower in non myelinated neurons. In many different demyelinating neuropathies, this insulation is lost. This causes a lack of nerve transmission. Schwann cells may be damaged by autoimmune disorders or toxic attack such as in Guillain-Barré syndrome and diphtheria. Diphtheria toxin causes loss of myelin by interfering with the production of proteins by the Schwann cells that produce and maintain myelin in the PNS. Triethyltin (A biocide chemical) which interrupts the myelin sheath around peripheral nerves is also known to induce demyelination.


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
      So this paper under discussion, by Masaki etal provides some insight. The paper mainly shows that the leprosy bacteria is able to induce a stem cell like condition into the schwann cells. The mechanism of how this is achieved is they turn off the specific factors that keep the cell in schwann cell lineage and then turn on the set of genes (embryonic and developmental genes, most importantly the HOX gene) that is expressed in a more pluripotent state. This plasticity makes the cell more of a "mesodermal like" condition that allows the pathogen dissociation more easily. The study also shows that such transformation can aid in the macrophage Granuloma formation.

    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

Further Reading:

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

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