Phase-variable capsular polysaccharides and lipoproteins modify bacteriophage susceptibility in Bacteroides thetaiotaomicron

A variety of cell surface structures dictate interactions between bacteria and their environment, including their viruses (bacteriophages). Members of the human gut Bacteroidetes characteristically produce several phase-variable capsular polysaccharides (CPS), but their contributions to bacteriophage interactions are unknown. To begin to understand how CPS impact Bacteroides-phage interactions, we isolated 71 B. thetaiotaomicron-infecting bacteriophages from two locations in the United States. Using B. thetaiotaomicron strains that express defined subsets of CPS, we show that CPS dictates host tropism for these phages and that expression of non-permissive CPS variants are selected under phage predation, enabling survival. In the absence of CPS, B. thetaiotaomicron escapes bacteriophage predation by altering expression of 8 distinct phase-variable lipoproteins. When constitutively expressed, one of these lipoproteins promotes resistance to multiple bacteriophages. Our results reveal important roles for Bacteroides CPS and other cell surface structures that allow these bacteria to persist under bacteriophage predation and hold important implications for using bacteriophages therapeutically to target gut symbionts.