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Molecular recognition of bacterial cell wall peptidoglycans and related molecules by innate immune receptors (PGN-INNATE)
Start date: Jan 1, 2014, End date: Jan 1, 2019 PROJECT  FINISHED 

The immune system of higher organisms is using pattern recognition receptors (PPR) of the host cell to fight pathogenic bacteria by recognizing molecular signatures called Pathogen Associated Molecular Patterns (PAMP) 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 PAMPs. Fragments of PGN and related small molecules can also elicit immune response i.e., act as PAMPs. Although the mechanism of action of PGNs leading to immunostimulation in the host is not yet completely understood, it has been shown that several families of PRRs mediated PGN recognition such as the Toll-like receptors and the recently discovered family of Peptidoglycan Recognition Proteins. 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 MR is considered as a ‘non-canonical’ PRR able to bind endogenous molecules as well as pathogens that mediates physiological clearance and acts as a bridge between homeostasis and immunity. However, the function of MR in host defense is not yet clearly understood. This proposal is aimed at investigating the molecular recognition of PGNs and related molecules by the PPRs at the molecular level using a combination of experimental and computational approaches such as Nuclear Magnetic Resonance (NMR) spectroscopy, Isothermal Titration Calorimetry (ITC), Surface Plasmon Resonance (SPR) and molecular docking calculations. These findings will provide an increased understanding of the molecular recognition by these innate immune receptors and could therefore form a basis of designing improved immunomodulators used as vaccine adjuvants or in the treatment of inflammatory diseases, to aid cancer treatments, to help organ transplants or to fight increasingly resistant inflections.
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