Associate Microbiologist, Department of Medicine
Brigham and Women's Hospital

lcomstock@channing.harvard.edu

The long term goals of the laboratory are to elucidate mechanisms used by members of the intestinal microbiota to establish and maintain symbiotic relationships in the mammalian intestine. Using Bacteroides fragilis as a model intestinal commensal, we have shown that the organism demonstrates extensive diversity of its surface polysaccharides and proteins. A single B. fragilis strain is able to synthesize at least eight distinct capsular polysaccharides, termed PSA through PSH, each of which is able to undergo a process of phase variation whereby their expression is either ON or OFF. We have shown that for seven of these polysaccharides, the mechanism of phase variation is the inversion of DNA segments containing the promoters of the polysaccharide biosynthesis operons. We have demonstrated that a single DNA invertase, designated Mpi, is responsible for 13 distinct DNA inversions throughout the B. fragilis chromosome including those controlling polysaccharide biosynthesis. Our continuing studies include determining the benefit that phase variation of surface molecules provides the organism for its survival in the mammalian intestine.

B. fragilis is also an important opportunistic pathogen involved in the production of intraabdominal abscesses following leakage of the colonic contents into the otherwise sterile peritoneal cavity. Our laboratory is investigating the genetic factors that contribute to abscess formation. We have shown that a mutant that lacks only PSA is severely attenuated for abscess formation. The zwitterionic nature of PSA, having both a positive and negative charge per repeating unit, is responsible for the abscessogenic potential of this molecule. Our continuing studies are aimed at analyzing conserved gene products that contribute to the charge motif of PSA. Despite the interstrain heterogeneity of the PSA structure, we predict that the charge motif is conserved and accounts for the abscessogenic potential of this species.

Coyne MJ, Reinap B, Lee MM, Comstock LE 2005. Human symbionts use a host-like pathway for surface fucosylation. Science. 2005 Mar 18;307(5716):1778-81. [abstract]

Coyne MJ, Weinacht KG, Krinos CM, Comstock LE. 2003. Mpi recombinase globally modulates the surface architecture of a human commensal bacterium. Proc Natl Acad Sci. 100:10446-10451. [abstract]

Krinos CM, Coyne MJ, Weinacht, KG, Tzianabos AO, Kasper DL, Comstock LE. 2001. Extensive surface diversity of a commensal microorganism by multiple DNA inversions. Nature. 414:555-558. [abstract]

Coyne MJ, Tzianabos AO, Mallory BE, Carey VJ, Kasper DL, and Comstock LE. 2001. A polysaccharide biosynthesis locus required for virulence of Bacteroides fragilis. Infect Immun. 69:4342-50. [abstract]