Extensive DNA Inversions in the B. fragilis Genome Control Variable Gene Expression

Abstract

The obligately anaerobic bacterium Bacteroides fragilis, an opportunistic pathogen and inhabitant of the normal human colonic microbiota, exhibits considerable within-strain phase and antigenic variation of surface components. The complete genome sequence has revealed an unusual breadth (in number and in effect) of DNA inversion events that potentially control expression of many different components, including surface and secreted components, regulatory molecules, and restriction-modification proteins. Invertible promoters of two different types (12 group 1 and 11 group 2) were identified. One group has inversion crossover (fix) sites similar to the hix sites of Salmonella typhimurium. There are also four independent intergenic shufflons that potentially alter the expression and function of varied genes. The composition of the 10 different polysaccharide biosynthesis gene clusters identified (7 with associated invertible promoters) suggests a mechanism of synthesis similar to the O-antigen capsules of Escherichia coli.

Bacteroides: the Good, the Bad, and the Nitty-Gritty

“…There were genes for Hly type I secretion systems, which are similar to the hemolysin type I secretion system HlyDb from E. coli (288), or the type II general secretion pathway (54). The large quantity of enzyme-containing outer membrane vesicles produced by B. fragilis (185) suggests that this may be an important export pathway (54). The Bacteroides genome also contains large numbers of gene homologs of a variety of efflux pumps systems whose export functions have not yet been defined.…”

“…The genomic studies of B. fragilis did not show evidence of type III, IV, autotransporter, or two-partner secretion systems. There were genes for Hly type I secretion systems, which are similar to the hemolysin type I secretion system HlyDb from E. coli (288), or the type II general secretion pathway (54). The large quantity of enzyme-containing outer membrane vesicles produced by B. fragilis (185) suggests that this may be an important export pathway (54).…”

“…The completion of the sequencing projects for B. thetaiotaomicron in 2003 (306) and B. fragilis in 2004 to 2005 (54,138) and subsequent proteomic analyses have vastly added to our understanding of the manner in which these organisms adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense the nutrient available and tailor nutrient-metabolizing systems accordingly, (ii) multiple pump systems to rid the bacteria of toxic substances, and (iii) the ability to control the environment by interacting with the host immune system so that it controls other (competing) pathogens.…”

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

“…Pathogenic bacteria use the phase variability of gene expression to evade the host immune system. Based on sequence analysis and biochemical evidence, many type I and III enzymes of Bacteroides fragilis as well as Haemophilus, Helicobacter, Mycoplasma, and Neisseria species were found to be potentially phase variable (176)(177)(178)(179)(180)(181). The biological significance of R-M systems that exhibit phase variability is not completely understood.…”

“…(iii) Whole-genome sequencing of B. fragilis revealed that many R-M systems of bacteria undergo inversions (176). It has been proposed that phase variation in these bacteria increases the diversity of R-M systems, generating up to eight different recognition subunits (176 (180,181).…”