| Nongroupable Neisseria meningitidis are frequently (up to 50%) isolated from the nasopharynx of asymptomatic human carriers, but are rarely (≤1%) isolated from sterile sites, such as cerebrospinal fluid and blood, in patients with invasive meningococcal disease. This dissertation defines the genetic basis for nongroupable isolates of N. meningitidis from human carriers and patients with invasive meningococcal disease.; In this body of work, the study of a population-based collection of nongroupable nasopharyngeal isolates (n = 60) identified three general genetic mechanisms of nongroupability. No evidence for novel serogroups was found. Class I isolates contained confirmed or presumed point mutations in genes required for capsule expression or assembly. Class II isolates harbored insertion elements in the biosynthesis locus, which were often accompanied by the import of foreign nucleotide sequences and major deletions. Class III isolates had a N. gonorrhoeae/N. lactamica arrangement, with tex adjacent to galE and no capsule genes intervening. Isolates that contained the serogroup Y synF capsule polymerase gene clustered by multilocus enzyme electrophoresis and multilocus sequence typing into the ET-508/ST-23 clonal complex (genetic distance ≤0.21), while the Class III isolates were members of the ST-198 clonal complex (genetic distance ≤0.25). These data indicate that invasive clones can be carried in the nasopharynx as nongroupable isolates. Further, inter-host survival of meningococci may not require expression of capsule.; The investigation of 18 nongroupable invasive isolates of N. meningitidis collected from diverse geographic settings gave similar results. All isolates were rapidly killed by normal human sera. Eight isolates held confirmed or presumed point mutations in genes required for capsule expression or assembly, similar to the Class I nasopharyngeal nongroupable isolates. Seven of these eight isolates contained the serogroup Y synF polymerase gene and were confirmed by whole-cell ELISA not to express capsule; the eighth isolate was likely nongroupable due to slipped-strand mispairing within the serogroup B synD polymerase gene. Nine isolates contained IS1301 insertions in the biosynthesis operon, often in association with foreign DNA and major deletions, similar to the Class II nasopharyngeal nongroupable isolates. (Abstract shortened by UMI.)... |
