New hope for leprosy?
Despite a World Health Organization resolution to eliminate leprosy by 2000, this disease remains prevalent with up to 500,000 new cases reported annually. Leprosy is a chronic neurodegenerative disease that is caused by the obligate intracellular pathogen Mycobacterium leprae. Much of the nerve damage caused by the infection is the result of M. leprae triggering extensive demyelination of Schwann cells in peripheral nerves. Recent evidence indicates that the demyelination in the early stages of the infection could be caused directly by the pathogen, rather than by an immunological response to it, because the binding of M. leprae to the surface of myelinating Schwann cells in culture causes the cells to demyelinate.
Recent work by shows that a direct mechanism of demyelination induced by M. leprae depends on the binding of the bacterium to the receptor tyrosine kinase ErbB2 on Schwann cells and the resulting activation of the Ras-Raf-MEK-ERK pathway. These findings have relevance for the potential treatment of leprosy and they highlight parallels between the dedifferentiation signal in leprosy and that in nerve injury and cancer.
The current treatment protocols for leprosy patients involve long-term treatment with multiple antibiotics. Whereas eradication of the pathogen is likely to remain the ideal and most cost-efficient regimen, it might also be beneficial to add a drug that can block the early pathogen-induced demyelination, such as Herceptin, PKI166 or other ErbB2 inhibitors.
Treating leprosy: an Erb-al remedy?
Trends Pharmacol Sci. 2007 28: 103-105
The latest leprosy situation can be obtained from the WHO website, http://www.who.int/lep, which indicates a global registered prevalence at the end of 2006 of around 225,000 cases, and new case detection in 2006 of around 259,000 cases. It may be interesting to note on your site that leprosy is curable within 6-12 months using multidrug therapy (MDT) supplied to all countries free of charge by WHO since 1995.
Best regards.
The research discussed here, relating to direct toxicity of M. leprae to nerves and resulting in rapid and massive demyelination, is based largely on tissue culture systems and limited observations in one strain of knock-out mice. The observations are intriguing from a neuroscience perspective, but great caution is required in extrapolating them to human leprosy. For example, nu-/nu- (nude) mice and intact Balb/c mice, as well as several cytokine knock-out mice, are routinely inoculated with high doses of M. leprae, and none have developed demyelination. In addition, other investigators using the same cell culture systems have not observed the extensive demyelination that has been described. If limited contact with M.leprae caused the same rapid and severe demyelination in man as is described in these experimental systems, then many leprosy patients would have no myelinated axons remaining in their bodies. This is not the case – demyelination occurs in focal sites in particular peripheral nerves. In patients with the most bacilli, nerves are often heavily infected but continue to be partially functional for many years – demyelination apparently progresses slowly even in these directly infected nerves. All investigators in this field agree that it would be highly desirable to find additional pharmacological interventions to specifically protect nerves in this disease. However, it is highly premature at this time, based on the limited and unconfirmed evidence mentioned, to suggest that blockers of the Ras-Raf-MEK-ERK pathway (or any other signaling pathway) will
accomplish this. Considerably more information is needed about the multiple mechanisms operating in the peripheral nerve infected by M.leprae before it is possible to make a rational selection of mechanisms to be enhanced or inhibited in order to limit the nerve damage that occurs in leprosy.
David Scollard, M.D., Ph.D., and
James Krahenbuhl, Ph.D.
National Hansen’s Disease Programs
Baton Rouge, LA