Structural basis of virus-bacteria dynamics in the human gut (360G-Wellcome-314669_Z_24_Z)

The human gut microbiome harbours trillions of bacteria and their viruses (bacteriophage), engaged in a continual arms race to develop resistance mechanisms and counter-adaptations. Bacterial capsules play a central role in this dynamic. Bacteriophage target capsular polysaccharides for infection, while bacteria employ phase-variable capsules as a defence mechanism. This interaction affects bacteria capsule phenotype, impacting bacterial interactions with the gut lining and immune system. Uncovering the molecular basis for this gut virus-bacteria dynamic is key in understanding the forces shaping gut bacterial populations, and their role in maintaining a healthy gut microbiome. Bacteroides, accounting for 25% of gut bacteria, and their bacteriophage, representing up to 95% of gut viruses, constitute the most prevalent virus-bacteria pair in the gut. In this study I will investigate the selection of bacterial capsules by bacteriophage with broad and narrow tropism for different Bacteroides thetaiotaomicron capsular polysaccharides. Using biochemical and biophysical approaches, including cryo-electron microscopy, my key goals are to: 1) Define the structural features driving selection in receptor binding proteins and capsular polysaccharides. 2) Elucidate glycan binding and cleavage mechanisms by receptor binding proteins during infection. 3) Identify the most active bacteriophage and proteins in altering Bacteroides capsule phenotype.