Enabling treatment for a neglected disease

Researchers at the MRC Centre for Medical Mycology discover that faulty signalling in the immune system of healthy individuals leads to Chromoblastomycosis.

Chromoblastomycosis is a chronic infection of the skin that is difficult to treat. It leads to raised crusted lesions affecting the skin and the layer of tissue that underlies the skin. It usually affects the limbs, and people can suffer with it for decades. Chromoblastomycosis is a non-lethal condition but was recently declared a neglected disease by the World Health Organization.

In response to this need, Professor Gordon Brown and his research team at the MRC Centre for Medical Mycology discovered that the reason underlying the susceptibility to disease (in healthy people) was defective immune recognition.

Before any immune mechanism can spring into action, the immune system needs to recognise that there is something for it to react against – including foreign material such as a virus, or in the case of Chromoblastomycosis, a fungal pathogen (a microbe capable of causing infection).

This kind of ‘immune recognition’ normally requires at least two sensing components, including ‘Toll-like receptors’ and ‘C-type lectin receptors’.  Toll-like receptors (TLRs) play very important roles in our immune systems by recognizing potentially harmful microbes and sending signals that trigger innate immune responses. Professor Brown was able to identify that in Chromoblastomycosis the TLR pathway was not operating as it should.

Cells respond to microbes through interactions between cellular receptors and microbial ligands, which act like a lock (receptor) and key (ligand). The research team demonstrated that if they added in a ‘missing’ microbial ligand to the TLR pathway, protective responses were restored, and the infection cleared.

This discovery enabled the effective treatment of this hitherto neglected disease. Very fortunately, a drug that was already licensed for use in people (imiquimod; a TLR ligand) proved to be highly effective when the research team tested it on a small cohort of people by topically applying the drug to the infected skin.

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