While working in rural India as a member of Doctors Without Borders, a young physician was assigned a mother and her nine year old son. The boy had a severe laceration on his foot, and it had become infected. While treating the wound, the doctor noticed several patches on the boy's elbows and knees where the skin was lighter than his normal skin color. These patches were raised, red lesions with clearly defined borders. The boy claimed to have no sensation in the affected areas, and admitted to reduced sensation in his feet as well. Upon further examination, the doctor noticed enlarged nerves in the lower legs, along with some evidence of drop foot.
Retrieval of patient history revealed that the boy lived in a small house with his mother, father and three older siblings, along with both maternal and paternal grandparents. The grandfather on the mother's side had died five years earlier, and had suffered from untreated leprosy. Being from a rural part of India, the boy did not always receive proper nutrition, and sanitation conditions in the slum his family lived in were deplorable.
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This history indicated a familial history of leprosy, along with prolonged exposure to an individual suffering from the disease. As the bacterium is typically transferred via aerosol from an infected person, the boy could very easily have come into contact with the pathogen from his grandfather. The lack of proper nutrition and the poor sanitation may have increased his susceptibility as well.
Fresh from medical school and aware that he was in a region where leprosy was endemic, the description of the lesions, loss of sensation, and the patient's medical history, led the doctor to diagnose the child with leprosy. In order to determine the specific type, he ordered a skin biopsy of the lesions. Histological acid fast stain showed of Mycobacterium leprae in the lesions. The presence of the bacteria indicates that the boy suffers from multibacillary leprosy (also known as lepromatous leprosy), the more serious, aggressive form of the disease.
M. leprae is transmitted via aerosol, entering via the mucous membranes, and from there the lymph and blood vessels, to reach its preferred targets, the nerves and the associated Schwann cells. Although Schwann cells are preferred, the bacteria also readily infect macrophages and endothelial cells. The bacteria seem to prefer areas cooler than the core body temperature, and so primarily infects cells that lie near the skin surface. M. leprae is an obligate intracellular parasite, and therefore must enter a host cell to replicate. Invasion begins with the organism binding to receptors on the host cell. Studies have shown that there are several binding sites that can be used by M. leprae, meaning that if one receptor is not present, others can be used in its place. (1)
On macrophages, M. leprae binds to the complement receptors CR1, and 4, and C3, via the PGL-1 peptide on its surface, which facilitates phagocytosis via the classical complement pathway. As a result of the binding to the C3 receptor, M. leprae being phagocytized into macrophages is not accompanied by a bacteria-destroying oxidative burst. This lack may be in indication that M. leprae is somehow able to alter or evade the initial cellular response to pathogens (4).
Once binding has occurred and the oxidative burst avoided, M. leprae moves into the host cell via phagocytosis within a phagosome. Then, the bacteria must survive the merging of the phagosome and lysosome, and live long enough to replicate then get back out of the cell. It is thought that the organism's phthiocerol-containing lipid capsule may play a large role in its intracellular survival. This capsule is the organism's primary virulence factor. (2) Some research has shown that M. leprae is somehow able to halt the lysosome fusion process for up to four hours, and actually replicate inside the phagosome (2, 3). The specific mechanisms by which the organism prevents fusion are still largely unknown. Regardless of mechanism, this process allows the bacteria to create a region directly surrounding itself where it is safe from the immune response, called the "electron transparent zone", because of its transparency under electron microscopy (2).
The organism cannot remain there indefinitely, though. After a certain period of time, or if the macrophage is activated, the macrophage or Schwann cell will introduce proteases directly into the phagosome, along with a large number of MHC molecules. This second cellular response is the primary defense against M. leprae. With a properly functioning immune system, the bacteria will be broken up into pieces. The MHC molecules can then take up those antigenic pieces, and present them on the membrane of the cell (5). However, if the bacterium can evade the degrading mechanisms and succeeds in replicating inside the cell, M. leprae will form a bundle of bacteria that then break out of the cell and go on to infect other tissue.
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This invasion, replication, and exit from target cells somehow results in injury to neurons, but the exact process is currently unknown. Furthermore, Mycobacterium leprae has never been cultured in vitro, which adds to the lack of information concerning the specific mechanisms the bacteria employs(1).
When the bacteria leave the Schwann cell or macrophage, it may penetrate the perineural tissues, and eventually form granulomas, the type of which depends on the type of leprosy. Epithelioid granules are present in tuberculoid leprosy, while lepromatous granulomas are indicative of lepromatous leprosy, the difference being the type of cells contained in the granuloma. The type of leprosy is, in turn, determined by the function of macrophages. In lepromatous leprosy, the host's macrophages are defective, and may only partially destroy M. leprae, while in tuberculoid leprosy, these cells ingest and completely annihilate the bacilli, which is why the organism will not be seen in biopsies of the lesions. In both cases, leprosy is basically a delayed type hypersensitivity reaction. The majority of the damage done in leprosy is caused by the host's own immune system overreacting to the presence of M. leprae antigen. The lepromatous form of leprosy is more severe because that antigen remains in the system, with periodic reemergence. This is also the reason that the vast majority of people are not susceptible to this disease. Their immune system destroys the invading organism with a moderate immune response, without causing undue harm to the surrounding cells. Most people who come into contact with M. leprae never even know they were infected.
The treatment recommended by the World Health Organization (WHO) is a combination of antibacterial drugs, including rifampicin, clofazimine and dapsone for lepromatous leprosy patients and rifampicin and dapsone for tuberculoid leprosy patients. Of these, rifampicin is the most important, and therefore is included in the treatment of both types of leprosy. Treatment of leprosy with only one anti-leprosy drug will always result in development of drug resistance to that drug. Treatment with dapsone or any other anti-leprosy drug used by itself should be considered as unethical. Rifampicin is given once a month, while clofazimine and dapsone are most active when administered daily. None of these drugs have serious side effects, but dapsone has been known to cause allergic reactions, especially in people allergic to sulfa drugs. For lepromatous leprosy, drug therapy will continue for twelve months to ensure complete eradication of the bacteria. (6)
Given the antibiotics available today, leprosy is completely curable. However, the cosmetic deformities and nerve damage that occur during the course of the disease are often irreversible. Extensive physical therapy may be able to regenerate some nerve damage and return some range of motion, but lost sensation almost never returns. This poses the greatest danger to those recovered from leprosy. Patients must be taught how to care for limbs they have difficulty feeling, similar to diabetics with nerve damage. If not taken care of, small cuts can become infected and fester. In this case study, the disease was caught at a stage where the boy should not be too adversely affected. Unless he undergoes physical therapy (which is unlikely in this situation), he may have some difficulty walking, and the lesions that were already present may leave scars, but he should emerge otherwise unharmed. Leprosy is rarely an immediate cause for death. The mortality rate for those with lepromatous leprosy is roughly four times greater than that of the general population, but this is mostly due to indirect effects of the disease.
Barker, L. 2006. Mycobacterium leprae interactions with the host cell: recent advances (Review article). Indian J Med Res, 123: 748-59.
Frehel, C., and Rastogi, N. 1987. Phagosome-lysosome fusion inhibition event. Infect Immun, 55.12: 2916-21.
Jameway, C. A., Travers, P., Walport, M., and Shlomchik, M. J. Immuno Biology: The immune system in health and disease. 6th Ed. Garland Science Publishing, New York:2005.
Schlesinger, L. S., and Horwitz, M. A. Phenolic Glycolipid-1 of Mycobacterium leprae binds complement component of C3 in serum and mediates phagocytosis by human monocytes. J Exp Med, 174: 1031-38.
Steinhoff, U., Golecki, J. R., Kazda, J., and Kaufmann, S. H. E. 1989. Evidence for phagosome-lysosome fusion in mycobacterium leprae-Infected murine schwann cells. Infect Imm, 57.3:1008-1010.
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World Health Organization. 2010. WHO Multidrug therapy (MDT). Retrieved May 5, 2010, from http://www.who.int/lep/mdt/en/