The immune system of higher organisms is using innate immune receptors to fight pathogenic bacteria by recognizing molecular signatures unique to the bacteria but absent from the host. Bacterial cell wall peptidoglycan (PGN), a polymer of disaccharide-pentapeptide repeating units, is one of the most important molecular patterns recognised by innate immune receptors. PGN can stimulate immune defences even without the presence of an infection, therefore it can act as a very potent adjuvant, which is a crucial component of vaccines. Unfortunately, PGN in traditional vaccines has too many side effects to be used in humans, however, its fragments and derivatives can also elicit immune response.
The mechanism of action of PGNs leading to immunostimulation is not yet completely understood, although it has been shown that several families of innate immune receptors mediated PGN recognition such as the Toll-like receptors, the NOD-like receptors and the recently discovered family of Peptidoglycan Recognition PRoteins. Furthermore, immunological studies of mannosylated PGN fragments indicated that the Mannose Receptor could also be involved in the recognition of mannosylated or even unmodified PGN fragments.
The aim of this proposal is investigating the molecular recognition of PGNs and related molecules by innate immune receptors at the molecular level using a combination of NMR spectroscopy and computational methods. We wish to investigate the involvement of the Mannose REceptor in PGN recognition, which has not been shown to date.
These findings will provide an invreased understanding of the molecular recognition of PGN by innate immune receptors and could therefore form a basis of desigining improved immunomodulators used as vaccine adjuvants or in other disease areas.