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Edited by Emil C. Gotschlich, The Rockefeller University, New York, NY, and approved March 7, 2017 (received for review December 20, 2016)
Significance
Neisseria meningitidis (Nm) remains a leading cause of meningitis and rapidly fatal sepsis in otherwise healthy individuals. Historically, Nm is not recognized as a significant cause of urogenital infections. Since 2015, a significant increase of meningococcal urethritis primarily among heterosexual men has been reported in multiple US cities. We defined that a unique nonencapsulated Nm clade, which belonged to the cc11/ET-15 hyperinvasive lineage, was linked to these Nm urethritis clusters. The clade isolates causing urethritis clusters in the United States may have adapted to the urogenital environment with two unique molecular fingerprints: the insertion of IS1301 with associated deletion of capsule, enhancing mucosal adherence, and the acquisition of the gonococcal denitrification pathway by gene conversion, promoting anaerobic growth.
Abstract
Neisseria meningitidis (Nm) clonal complex 11 (cc11) lineage is a hypervirulent pathogen responsible for outbreaks of invasive meningococcal disease, including among men who have sex with men, and is increasingly associated with urogenital infections. Recently, clusters of Nm urethritis have emerged primarily among heterosexual males in the United States. We determined that nonencapsulated meningococcal isolates from an ongoing Nm urethritis outbreak among epidemiologically unrelated men in Columbus, Ohio, are linked to increased Nm urethritis cases in multiple US cities, including Atlanta and Indianapolis, and that they form a unique clade (the US Nm urethritis clade, US_NmUC). The isolates belonged to the cc11 lineage 11.2/ET-15 with fine type of PorA P1.5–1, 10–8; FetA F3-6; PorB 2–2 and express a unique FHbp allele. A common molecular fingerprint of US_NmUC isolates was an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. This resulted in the loss of encapsulation and intrinsic lipooligosaccharide sialylation that may promote adherence to mucosal surfaces. Furthermore, we detected an IS1301-mediated inversion of an ∼20-kb sequence near the cps locus. Surprisingly, these isolates had acquired by gene conversion the complete gonococcal denitrification norB-aniA gene cassette, and strains grow well anaerobically. The cc11 US_NmUC isolates causing urethritis clusters in the United States may have adapted to a urogenital environment by loss of capsule and gene conversion of the Neisseria gonorrheae norB-aniA cassette promoting anaerobic growth.
Footnotes
- ↵1To whom correspondence should be addressed. Email: dstep01{at}emory.edu.
Author contributions: Y.-L.T. and D.S.S. designed research; Y.-L.T. performed research; J.A.B., A.N.T., X.W., A.C.R., T.D.R., E.T., D.E.N., and C.D.R. contributed new reagents/analytic tools; Y.-L.T., A.C.R., T.D.R., and E.T. analyzed data; and Y.-L.T. and D.S.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the BioProject database (accession nos. PRJNA324131 and PRJNA319252).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1620971114/-/DCSupplemental.
Freely available online through the PNAS open access option.
N. meningitidis urethritis clade
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