How bacterial pathogens "sweeten" host proteins to avoid immunological responses: structural study of sugar transfer by bacterial virulence factors

Antimicrobial resistance is one of the biggest threats to global health. To reduce it, we must ensure that antibiotics are used only where appropriate. Accordingly, other non-antibiotic approaches are welcome, and a better understanding of the biology of bacterial infections is required. Pathogens such as Salmonella and E. coli inject virulence factors (effectors) to suppress antimicrobial host responses, to promote colonisation. The NleB effector is highly conserved among pathogens. It transfers GlcNAc sugar residues to host proteins (GAPDH, FADD, TRADD), a "sweet tag" that inhibits NF-kB activation and apoptosis of infected cells, blocking major antimicrobial host responses.
In this project, we will use advanced NMR spectroscopy, molecular modelling (protein-ligand docking, long molecular dynamics simulations), and other biophysical techniques (ITC) to unveil the structural features at atomic detail of the molecular recognition of host proteins by the bacterial effectors NleB1, SseK1, and SseK2. Members of this conserved family modify different host proteins and exhibit distinct modes of action to suppress host responses, but, interestingly, they differ only in a very small number of amino acids. We will try to rationalise the molecular basis of their exquisite selectivity, and the impact of sugar transfer on the interactions with other host proteins such as TRAF2.