Continuing genomic evolution of the Neisseria meningitidis cc11.2 urethritis clade, Nm UC: a narrative review

Abstract

Neisseria meningitidis (Nm) is a bacterial pathogen responsible for invasive meningococcal disease. Though typically colonizing the nasopharynx, multiple outbreaks of meningococcal urethritis were first reported in 2015-2016; outbreaks originally presumed to be caused by Neisseria gonorrhoeae (Ng). Genomic analysis revealed that the Nm isolates causing these outbreaks were a distinct clade, and had integrated gonococcal DNA at multiple genomic sites, including the gonococcal denitrification apparatus aniA-norB, a partial gonococcal operon of five genes containing ispD, and the acetylglutamate kinase gene argB with the adjacent gonococcal locus NGO0843. The urethritis isolates had also deleted the group C capsule biosynthesis genes cssA/B/C and csc, resulting in loss of capsule. Collectively, these isolates form the N. meningitidis urethritis clade (NmUC). Genomic analysis of recent (2016-2022) NmUC isolates revealed that the genomic features have been maintained in the clade, implying that they are important for NmUC's status as a urogenital pathogen. Furthermore, the analysis revealed the emergence of a sub-clade, designated NmUC-B, phylogenetically separated from the earlier NmUC-A. This sub-clade has integrated additional gonococcal alleles into the genome, including alleles associated with antimicrobial resistance. NmUC continues to adapt to a urethral niche and evolve as a urogenital pathogen.

Keywords: Neisseria gonorrhoeae; Neisseria meningitidis; NmUC; antimicrobial resistance; genomic evolution; urogenital pathogen.

Fig. 1.

(a) The gonococcal denitrification apparatus in NmUC. The Nm ancestor of NmUC underwent homologous recombination with Ng DNA, integrating the gonococcal norB-aniA cassette into the genome, bolstering denitrification and microaerobic respiration. Panel (a) is a modification of Fig. 2a in [38]. (b) The gonococcal ispD operon in NmUC. The homologous recombination with Ng DNA integrated five genes (ispD was partial recombined) of a larger nine-gene operon into the genome and acquired gonococcal alleles. (c) The argB and NGO0843 genes in NmUC. The gonococcal argB and NGO0843 (encoding a hypothetical protein) genes were integrated into the Nm ancestor genome. The two loci were only partially recombined, and the integration of NGO0843 resulted in an alternative stop codon and a longer coding sequence than that found in Ng.

Fig. 2.

SNP-based phylogeny of NmUC isolates. NmUC isolates (n=261) and a comparison group of non-clade lineage 11.2 Nm (n=39) are included. Isolates are marked at the tip and inner column for the country of origin, the second column for year of isolation and the outer column for the grouping of isolates. The NmUC-B branch in the phylogenetic tree is also outlined in red to highlight this emerging sub-clade. In the legend, the bracketed numbers denote the number of isolates in each category.

Fig. 3.

SNP density plots of new SNP regions defining the 40 NmUC-B sub-clade isolates. Core genomes were aligned with isolate CNM3 set as the reference genome, as CNM3 has the standard (most abundant) alleles for each of the new characteristic regions of NmUC-B. Each SNP that differs from CNM3 is shown as a single line, and multiple neighbouring SNPs appear as thick lines. The light-grey region indicates that sequence is absent in one or more of the aligned genomes. One representative region from each category in Table 3 is shown. (a) Region A, present in all 40 NmUC-B isolates. (b) Region G, present in mostNmUC-B isolates. (c) Region L, present in a significant minority. Three isolates that have varied allele combinations of NEIS1320, NEIS1319 and NEIS2445 are plotted with allele numbers included, respectively, in parentheses.