Mutator clones of Neisseria meningitidis in epidemic serogroup A disease

Serogroup A Neisseria meningitidis has repeatedly caused widespread epidemics of meningitis and septicemia throughout the 20th century. Recently, in a limited collection of strains, epidemic serogroup A isolates were found to have elevated mutation rates that was caused by defects in mismatch repair pathways. To ascertain the role of these mutators in the epidemic spread of this serogroup, the prevalence of hypermutability in a collection of 95 serogroup A N. meningitidis invasive isolates was determined. Overall mutability in Neisseriae can be described by measuring both missense mutation rates as well as phase variation frequencies of “contingency loci.” Fifty-seven percent of serogroup A isolates possessed elevated mutability, which could be divided into two classes: intermediate and high level. Eleven of 20 high-level mutators, with phase variation rates >100-fold higher than wild-type isolates, were defective in mismatch repair. Ten of the 34 intermediate mutators possessing >10-fold increases in phase variation rates could be partially complemented by a wild-type mutL allele. A high prevalence of mutators in epidemic isolates indicates that hypermutability may play a major role in the transmission of this pathogen. The added diversity derived from increased phase variation rates may allow fixation of mutator alleles more frequently during epidemic spread.

A群血清型脑膜炎奈瑟菌（Neisseria meningitidis）在整个20世纪期间多次引发脑膜炎与败血症的大规模流行。近期，在针对有限菌株集合的研究中，研究者发现流行株A群分离株存在突变率升高的现象，该现象由错配修复通路（mismatch repair pathways）缺陷所导致。为明确此类高突变株在该血清群流行传播中的作用，本研究针对95株A群血清型脑膜炎奈瑟菌侵袭性分离株集合，测定了其中高突变性（hypermutability）的流行率。奈瑟菌属的整体突变性可通过测定错义突变率（missense mutation rates）与“偶然性基因座（contingency loci）”的相变异频率来表征。57%的A群血清型分离株存在突变率升高的情况，可分为两个等级：中等水平与高水平。20株高水平高突变株中，有11株的相变异速率较野生型分离株高出100倍以上，且存在错配修复缺陷。34株相变异速率提升10倍以上的中等水平高突变株中，有10株可通过野生型mutL等位基因（mutL allele）实现部分功能互补。流行株分离株中高突变株的高流行率表明，高突变性可能在该病原菌的传播过程中发挥关键作用。相变异速率提升所带来的额外遗传多样性，或可使高突变等位基因在流行传播过程中更易被固定。