Expansion of a urethritis-associated Neisseria meningitidis clade in the United States with concurrent acquisition of N. gonorrhoeae alleles

Abstract

Background: Increased reports of Neisseria meningitidis urethritis in multiple U.S. cities during 2015 have been attributed to the emergence of a novel clade of nongroupable N. meningitidis within the ST-11 clonal complex, the "U.S. NmNG urethritis clade". Genetic recombination with N. gonorrhoeae has been proposed to enable efficient sexual transmission by this clade. To understand the evolutionary origin and diversification of the U.S. NmNG urethritis clade, whole-genome phylogenetic analysis was performed to identify its members among the N. meningitidis strain collection from the Centers for Disease Control and Prevention, including 209 urogenital and rectal N. meningitidis isolates submitted by U.S. public health departments in eleven states starting in 2015.

Results: The earliest representatives of the U.S. NmNG urethritis clade were identified from cases of invasive disease that occurred in 2013. Among 209 urogenital and rectal isolates submitted from January 2015 to September 2016, the clade accounted for 189/198 male urogenital isolates, 3/4 female urogenital isolates, and 1/7 rectal isolates. In total, members of the clade were isolated in thirteen states between 2013 and 2016, which evolved from a common ancestor that likely existed during 2011. The ancestor contained N. gonorrhoeae-like alleles in three regions of its genome, two of which may facilitate nitrite-dependent anaerobic growth during colonization of urogenital sites. Additional gonococcal-like alleles were acquired as the clade diversified. Notably, one isolate contained a sequence associated with azithromycin resistance in N. gonorrhoeae, but no other gonococcal antimicrobial resistance determinants were detected.

Conclusions: Interspecies genetic recombination contributed to the early evolution and subsequent diversification of the U.S. NmNG urethritis clade. Ongoing acquisition of N. gonorrhoeae alleles by the U.S. NmNG urethritis clade may facilitate the expansion of its ecological niche while also increasing the frequency with which it causes urethritis.

Keywords: Gene transfer; Genital disease; Neisseria gonorrhoeae; Neisseria meningitidis; Speciation.

Fig. 1

SNP parsimony phylogeny of 353 N. meningitidis isolates. Isolates are marked to indicate the serogroup (inner ring), year of isolation (second ring), whether collected in the USA (third ring), the body site from which they were isolated (outer ring), and whether the patient was a MSM (circles on branch tips). Counts in the key refer to isolates outside of the U.S. NmNG urethritis clade. The 209 isolates of the U.S. NmNG urethritis clade are collapsed, with details presented in Fig. 2. Additional labels identify the lineage 11 branch, the branches for sublineages 11.1 and 11.2, two European isolates from MSM that are closely related to U.S. isolates from MSM (asterisks), and two closely related NmNG urethritis isolates within sublineage 11.2 (blue star). The scale bar represents 250 substitutions within the 8607 core SNP alignment

Fig. 2

Time-measured Bayesian phylogeny U.S. NmNG urethritis clade. The analysis included 204 isolates belonging to the clade, with nine closely related invasive isolates used as an outgroup. Isolates are marked according to the state in which they were isolated (symbols on branch tips), and body site from which they were isolated (colored ring). Counts in the key refer to isolates in the U.S. NmNG urethritis clade. Nodes mentioned in the text are marked with black circles and labeled with the estimated year: (a) the root; (b) divergence between urethritis clade and NmC isolates, (c) the U.S. NmNG urethritis clade; and (d) the clade comprising solely isolates from Columbus, OH. The two branches originating at the root (node “a”) are dashed to indicate that inferred mutational events on the branch leading to the outgroup cannot be oriented with respect to time. The scale bar represents 1 year

Fig. 3

Gonococcal DNA content of U.S. NmNG urethritis clade isolates and closely related invasive isolates. Sequence change is measured relative to M21273 and plotted with respect to the date of isolation. Isolates collected before 2012 are not part of the U.S. NmNG urethritis clade