Mismatch repair and virulence

Abstract

Neisseria meningitidis can produce such an extensive variation of adhesive, invasive and antigenic properties that a single infecting organism can give rise to diverse populations with very different virulence properties. Such a strategy increases the probability of generating a variant that is better adapted to the new host. The variability of N. meningitidis virulence determinants is generated very efficiently by frame-shift mutagenesis in chromosomal regions containing repeated nucleotide tracts called contingency loci. The frequency of such mutagenesis among N. meningitidis clinical isolates is highly variable. For example, the frequency of phase variation in hemoglobin (Hb) receptors among clinical isolates of serogroups A, B and C ranges from 10−6 to 10−2.Now, Richardson and Stojiljkovic 1xMismatch repair and the regulation of phase variation in Neisseria meningitidis. Richardson, A.R. and Stojiljkovic, I. Mol. Microbiol. 2001; 40: 645–655Crossref | PubMed | Scopus (95)See all References1 have suggested that the frequency of phase variation might be genetically determined for a particular strain, as they found two unlinked Hb receptors underwent phase variation with similar frequencies within a given isolate. They also observed that an increase in the frequency of phase variation was often accompanied by high rates of base-substitution mutations conferring resistance to rifampicin and nalidixic acid. This formidable genetic instability was shown to be a consequence of defects in the mismatch-repair genes. Inactivation of mismatch repair increases the Hb switching frequency 250–500-fold and base substitution mutagenesis 20–30-fold. These results, together with the previous observation that Pseudomonas aeruginosa strains isolated from lungs of cystic fibrosis patients have a very high frequency of mismatch-repair-deficient mutants, which were much more resistant to antibiotics than non-mutated pathogenic isolates 2xHigh frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Oliver, A. et al. Science. 2000; 288: 1251–1254Crossref | PubMed | Scopus (811)See all References2, suggest that high mutation rates could increase the virulence of pathogenic strains.