Pattern recognition receptor co-stimulation and chronic fungal infection in chromoblastomycosis. (360G-Wellcome-092976_Z_10_Z)

Fonseca pedrosoi is a causative agent of chromoblastomycosis, a chronic disfiguring disease of the skin and subcutaneous tissues which is very difficult to treat. Virtually nothing is known about the immunology underlying this disease or why it causes chronic infections. Using murine models, we have discovered that the chronicity of the systemic disease is due to a defect in innate recognition. We found that although the pathogen was recognised by an unidentified Fc(gamma)-coupled receptor, it did not co-activate the Toll-like receptor pathway, which resulted in an insufficient pro-inflammatory response. Excitingly, infection could be cured in vivo by artificially co-stimulating the TLR-pathway, suggesting a possible route for treatment of this disease in humans. In this application, we wish to verify that this form of treatment would work without undesirable side-effects in a murine subcutaneous infection model, which would more closely resemble the human disease, and to explore the possibility of using topically applied TLR agonists as a form of treatment. We also propose to characterise the innate mechanisms involved in the recognition of F. pedrosoi, by identifying the pattern recognition receptor(s) involved and by characterising the cell wall of this organism.