Principles of extra- and intracellular chitin perception by mammalian pattern recognition receptors

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Chitin, a hydrophobic polymer of β-1,4-linked N-acetylglucosamine (GlcNAc), is abundant in nature and can be found e.g. in the cell wall of fungi, the exoskeletons of arthropods such as crustaceans and insects, and nematodes. However, chitin does not exist in mammals and plants. In these organisms, chitin is a typical microbe-associated molecular pattern (MAMP), as evidenced by the existence of chitin-mediated activation of immune responses through pattern recognition receptors (PRRs). In humans the consequent PRR-mediated inflammatory responses have been associated with fungal infections and allergic asthma. During initial exposure, the mammalian host typically encounters chitin in a highly polymeric and insoluble form – e. g. fragments of the exoskeleton of house dust mites or the cell wall of pathogenic fungi like C. albicans or C. neoformans – and this polymeric insoluble chitin has been considered immunologically inert. However, we previously showed that in humans, sensing of soluble, oligomeric chitin is mediated by Toll-like receptor (TLR) 2 in immune cells, whereas work by others demonstrated FIBCD1 or LYSMD3 are involved in epithelial cells. We recently found that TLR2 signaling also employs LBP, CD14 and TLR1 and can be activated by diffusible ligands provided by the host endochitinase, CHIT1. These newly discovered sensing pathways are highly reminiscent of chitin perception in plants, where the cell-surface receptors CERK1 and its co-receptor CEBiP detect chitin oligomers generated by host chitinases. However, in the structure-function relationships (e.g. degree and pattern of acetylation) and the regulation of chitin sensing by the mammalian CHIT1-TLR system await systematic exploration for a better understanding and, possibly, targeting of extracellular chitin sensing. Moreover, recent advances in carbohydrate synthesis open the possibility for systematic analysis of custom-made, non-natural synthetic oligomers for agonistic and antagonistic immune-regulatory properties in mammalian systems. Finally, the intriguing notion of cytosolic chitin sensing in the context of intracellular fungal pathogens like C. neoformans remains open but could be vital for understanding immune responses triggered by intracellular fungal pathogens. Based on the preliminary data generated together with other consortium members and with further partnerships and tools available within this priority program, these open questions will be addressed in both human and murine cellular systems, hoping to delineate a ‘code’ of what determines extra- and intracellular immune stimulation by chitin in mammalia. The knowledge gained in the first funding phase could then be applied to explain and modulate/prevent immune reactions in the context of chito-based biomaterials and/or exploited to purpose-build materials with specific immune-agonistic or -antagonistic properties.