DIFFERENTIAL FLAGELLAR GLYCOSYLATION AMONG CLINICAL ISOLATES OF CLOSTRIDIUM DIFFICILE

John Costanza , Andrew E. Clark, Bryan P. Roxas, Shylaja Ramamurthy, VK Viswanathan, Gayatri Vedantam

DIFFERENTIAL FLAGELLAR GLYCOSYLATION AMONG CLINICAL ISOLATES OF CLOSTRIDIUM DIFFICILE

Clostridium difficile (CD) has recently emerged as the most common healthcare-associated infection and causes antibiotic-associated diarrhea, which imposes a 3 billion dollar burden annually to the US healthcare system.  Disease is mediated through the action of two well-characterized glucosylating toxins which target cellular GTPases resulting in fulminant diarrhea, and in severe cases, pseudomembranous colitis, toxic megacolon and death.  In contrast, events leading to CD host colonization remain largely uncharacterized.  The CD genome encodes a number of known and putative colonization factors including a type IV pilus, fibronectin binding proteins, and a flagellar system.  CD flagella are critical for bacterial motility and likely play a pivotal role in bacterial-host interactions.  We have visualized CD flagellar structures, which contain glycoproteins. In this study, we have identified and characterized a glycosylation island within the CD flagellar biosynthesis locus which is responsible for post-translational modification of the flagellin protein FliC.  DNA sequence analysis revealed that the genetic content of this glycosylation locus varies among CD strains from different lineages.  Mutagenesis of target genes within this locus demonstrated that glycosylation, at some level, was necessary for CD motility.  CD flagellar glycosylation mutants are currently being assessed for virulence in the hamster model of acute CDI, and this is also being tested in vitro for modulation of the host innate and adaptive immune responses.  Study support from NIH 1R01AI081742 and VA BX1I01BX001183.

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