21A variety of cell surface structures, including capsular polysaccharides (CPS), dictate 22interactions between bacteria and their environment including their viruses (bacteriophages). 23Members of the prominent human gut Bacteroidetes characteristically produce several phase-24 variable CPS, but their contributions to bacteriophage interactions are unknown. We used 25 engineered strains of the human symbiont Bacteroides thetaiotaomicron, which differ only in the 26 CPS they express, to isolate bacteriophages from two locations in the United States. Testing each 27 of 71 bacteriophages against a panel of strains that express wild-type phase-variable CPS, one of 28 eight different single CPS, or no CPS at all, revealed that each phage infects only a subset of 29 otherwise isogenic strains. Deletion of infection-permissive CPS from B. thetaiotaomicron was 30 sufficient to abolish infection for several individual bacteriophages, while infection of wild-type 31 B. thetaiotaomicron with either of two different bacteriophages rapidly selected for expression of 32 non-permissive CPS. Surprisingly, acapsular B. thetaiotaomicron also escapes complete killing 33 by these bacteriophages, but surviving bacteria exhibit increased expression of 8 distinct phase-34 variable lipoproteins. When constitutively expressed, one of these lipoproteins promotes 35 resistance to multiple bacteriophages. Finally, both wild-type and acapsular B. thetaiotaomicron 36 were able to separately co-exist with one bacteriophage for over two months in the mouse gut, 37suggesting that phase-variation promotes resistance but also generates sufficient numbers of 38 susceptible revertants to allow bacteriophage persistence. Our results reveal important roles for 39Bacteroides CPS and other cell surface structures that allow these bacteria to persist despite 40 bacteriophage predation and hold important implications for using bacteriophages therapeutically 41 to target gut symbionts. 42 43Bacteroides thetaiotaomicron and Bacteroides fragilis each encode 8 different CPS 14,15 and there 61 is broad genetic diversity of cps loci among different strains within these species (e.g., 47 62 different cps biosynthetic loci were identified in just 14 strains of B. thetaiotaomicron) 8 . In 63Bacteroides, CPS structures appear to surround the entire bacterial cell 16,17 and the cps 64 biosynthetic loci that encode these surface coatings are often under the control of phase variable 65 promoters 8,15,18 . In conjunction with other regulatory mechanisms, phase variable CPS 66 4 expression generates phenotypic heterogeneity within an otherwise isogenic population that may 67 facilitate survival in the face of diverse disturbances 8,15,19,20 . 68 Bacterial viruses or bacteriophages (herein, phages), like the bacteria on which they prey, 69 vary greatly across individual gut microbiomes and are even responsive to host dietary changes 70 and disease states [21][22][23][24][25] . Compared to gut bacteria, far less is understood about the phages of the 71 gut microbi...
39Efficient nutrient acquisition in the competitive human gut is essential for microbial 40 persistence. While polysaccharides have been well-studied nutrients for the gut microbiome, 41 other resources such as co-factors and nucleic acids have been less examined. We describe a 42 series of ribose utilization systems (RUSs) that are broadly represented in Bacteroidetes and 43 appear to have diversified to allow access to ribose from a variety of substrates. One Bacteroides 44 thetaiotaomicron RUS variant is critical for competitive gut colonization in a diet-specific 45 fashion. Using molecular genetics, we probed the nature of the ribose source underlying this diet-46 specific phenotype, revealing that hydrolytic functions in RUS (e.g., to cleave ribonucleosides) 47 are present but dispensable. Instead, ribokinases that are activated in vivo and participate in 48 cellular ribose-phosphate metabolism are essential. Our results underscore the extensive 49 mechanisms that gut symbionts have evolved to access nutrients and how metabolic context 50 determines the impact of these functions in vivo. 51 52 53 54 55
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