Molecular Sensing of Chitin by Toll-like Receptors

• Applicant: Professor Alexander Weber, Ph.D.
• Subject Area: Immunology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388534740

Fungal infections and allergic asthma cause death and suffering in millions of patients worldwide and critically involve pattern recognition receptors (PRR)-mediated immune control. Dectin-1 is a cell-surface PRR for the microbe-associated molecular pattern (MAMP) beta-1,3-glucan, which is a major structural cell wall component in fungi and triggers phagocytosis of fungal pathogens and protective inflammatory responses. However, the PRR for chitin, a beta-1,4-N-acetyl-glucosamine (NAG) component of fungal cell walls and house dust mite allergen has remained controversial and so far no direct binding studies have been published. TLR2 is known to initiate potent immune responses by recognizing di- and triacylated lipopeptides in complex with TLR6 or TLR1, respectively. Although no fungal TLR2 ligand has been identified to date, TLR2 has been strongly implicated in murine infection models of and human patients suffering from the major pathogens Aspergillus and Candida, as well as allergic asthma. We have now identified TLR2 as the PRR directly binding and signaling to chitin. We observe that, whereas chitin chains containing more than 6 NAGs potently activate various human and murine immune cells, fragments containing only 4 or 5 NAGs are immunologically inactive but possess antagonistic activity. However, the mechanistic basis and immunological significance for agonism or antagonism of chitin NAGs via TLR2 remains elusive and is to be addressed here. Additionally, it remains unclear how TLR2 lipopeptide and chitin recognition may show differences and/or similarities in TLR1, TLR6, or potentially TLR10, co-receptor usage and the immunological outcomes of stimulation or antagonism. Since chitin represents the second most abundant polysaccharide in nature, is an immuno-activatory component linked to multiple human disease, affects Th1/Th2 skewing of adaptive immune responses and represents a potential novel vaccine adjuvant unraveling these principles of chitin recognition, signaling and immuno-regulation is of high basic and therapeutic interest.

• DFG Programme: Research Grants