Comstock, Laurie E. A10441 93-A2 The Bacteroides are one of the numerically dominant genera of bacteria of the human intestinal microbiota where they are mutualistic symbionts providing beneficial properties to the mammalian host. If Bacteroides fragilis gains access to the otherwise sterile peritoneal cavity due to a reach in the intestinal barrier from natural, traumatic, or surgical circumstances, it can become an opportunistic pathogen. In fact, B. fragilis is one of the most commonly isolated anaerobes from clinical infections. The capsular polysaccharides of B. fragilis have been shown to be instrumental in the ability of this organism to both provide symbiotic benefits to the mammalian host in its natural intestinal niche, and to cause disease if it gains access to extraintestinal sites. Our objective is to understand how the complex set of capsular polysaccharides synthesized by B. fragilis is regulated to better appreciate their contributions to symbiosis and virulence.
The aims will address different levels of regulation of the synthesis of the capsular polysaccharides. In particular, Aim 1 will analyze the mechanisms governing the ability of a set of factors to repress transcriptional termination of their respective polysaccharide biosynthesis loci.
Aim 2 will analyze the mechanisms by which a set of novel transcriptional repressors are able to interfere with the expression of specific capsular polysaccharides.
Aim 3 will address the importance of the synthesis of an extracellular polysaccharide which we will analyze for functional contributions to symbiosis. Due to the importance of the capsular polysaccharides to both symbiosis and virulence, these combined studies will ultimately allow us to better understand how these microorganisms affect the host with either beneficial (probiotics, immune regulation and tolerance, and maturation of the epithelial surface) or deleterious (induction of abscess formation, transfer of antibiotic resistance and involvement in inflammatory bowel disease) effects.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Bacterial Pathogenesis Study Section (BACP)
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Korpela, Jukka K
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Brigham and Women's Hospital
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Wieland Brown, Laura C; Penaranda, Cristina; Kashyap, Purna C et al. (2013) Production of α-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol 11:e1001610
Chatzidaki-Livanis, Maria; Weinacht, Katja G; Comstock, Laurie E (2010) Trans locus inhibitors limit concomitant polysaccharide synthesis in the human gut symbiont Bacteroides fragilis. Proc Natl Acad Sci U S A 107:11976-80
Chatzidaki-Livanis, Maria; Coyne, Michael J; Comstock, Laurie E (2009) A family of transcriptional antitermination factors necessary for synthesis of the capsular polysaccharides of Bacteroides fragilis. J Bacteriol 191:7288-95
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Coyne, Michael J; Reinap, Barbara; Lee, Martin M et al. (2005) Human symbionts use a host-like pathway for surface fucosylation. Science 307:1778-81
Weinacht, Katja G; Roche, Hazeline; Krinos, Corinna M et al. (2004) Tyrosine site-specific recombinases mediate DNA inversions affecting the expression of outer surface proteins of Bacteroides fragilis. Mol Microbiol 53:1319-30
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