The major hypothesis of this proposal is that the polysaccharide capsules (CPS) of Campylobacter jejuni are virulence determinants of this important human pathogen. The CPS s are structurally diverse and subject to phase variable expression. In addition, there are modifications to the polysaccharides (e.g. methyl phosphoramidate or MeOPN) that are also subject to phase variation. A sub-hypothesis is that the ability to undergo phase variations in capsule expression and structure affords an advantage to C. jejuni by allowing it to modulate its surface charge and structure, and that differences in CPS structure among strains affect virulence. The goals of this project are to delineate the role or roles that CPS play in pathogenesis of C. jejuni diarrhea. Studies will also be done to determine signals that regulate expression of CPS and to determine when CPS is expressed during interaction with eukaryotic cells. Mutants will be constructed that express either no CPS or CPS with altered structure and the effects of these changes will be examined in in vitro and in vivo models of virulence. Purified CPS s of distinct structure will also be evaluated in in vitro models.
Although Campylobacter jejuni is a major cause of diarrheal disease worldwide, this organism has proven particularly refractory to studies of molecular pathogenesis. Capsules are one of the few virulence factors described in this pathogen and recent evidence suggests that they may be protective antigens. This proposal addresses the hypothesis that capsular polysaccharides play a key role in disease by C. jejuni and that structural changes in capsules modulate virulence. This would be consistent with epidemiological observations that certain capsule types are more prevalent in human disease.
