Influence of cell wall modifications by chitin deacetylases on the human immune response against Cryptococcus neoformans and other human pathogenic fungi

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Human pathogenic fungi can cause severe systemic infections, especially in immunocompromised people. The molecular mechanisms leading to an effective defence against the invading fungi are still poorly understood. Studies on Cryptococcus neoformans infections suggest that the composition of the cell wall is essential for the virulence of the fungus. Like some other pathogenic fungi, it has chitosan in its cell wall instead of chitin (poly-N-acetyl-glucosamine), which is produced by the partial deacetylation of nascent chitin by chitin deacetylases (CDAs). Oligomeric chitin was shown to act as a microbe-associated molecular pattern (MAMP) and is recognised by pattern recognition receptors such as Toll-like receptor 2 (TLR2), fibrinogen C domain containing 1 (FBCD1) or LYSMD3 of the human immune system. However, the conversion of chitin to chitosan by its four different CDAs (CnCDAs 1-4) may allow C. neoformans to evade recognition by the host immune system. The enzymes are considered to be important virulence factors of the pathogen, preventing the degradation of chitin by human chitinases to immunostimulatory oligomers. In the present project, we address this hypothesis as an interdisciplinary consortium by (1) analysing the substrate specificities of the fungal CnCDAs as well as the human chitinolytic enzymes chitotriosidase (ChT), acidic mammalian chitinase (AMCase) and lysozyme, (2) investigating the amount and structure of chitosans in the fungal cell wall of different human pathogenic fungi after in vitro cultivation or in materials from in vivo infections, and (3) test the immunostimulatory effect of chitosans and their enzymatic degradation products on epidermal and immune cells. The project will thus contribute to a better understanding of host-microbe interactions and the development of anti-infective strategies preventing fungal infections.