{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:11:03Z","timestamp":1772169063199,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.15333.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T00:00:00Z","timestamp":1564704000000}}],"reference-count":60,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T00:00:00Z","timestamp":1564704000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["109025"],"award-info":[{"award-number":["109025"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust","award":["087622"],"award-info":[{"award-number":["087622"]}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Expression of a capsule from one of serogroups A, B, C, W, X or Y is usually required for\n                    <ns4:italic>Neisseria meningitidis<\/ns4:italic>\n                    (\n                    <ns4:italic>Nme<\/ns4:italic>\n                    ) to cause invasive meningococcal disease. The capsule is encoded by the capsule locus,\n                    <ns4:italic>cps<\/ns4:italic>\n                    , which is proposed to have been acquired by a formerly capsule null organism by horizontal genetic transfer (HGT) from another species. Following identification of putative capsule genes in non-pathogenic\n                    <ns4:italic>Neisseria<\/ns4:italic>\n                    species, this hypothesis is re-examined.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    Whole genome sequence data from\n                    <ns4:italic>Neisseria<\/ns4:italic>\n                    species, including\n                    <ns4:italic>Nme<\/ns4:italic>\n                    genomes from a diverse range of clonal complexes and capsule genogroups, and non-\n                    <ns4:italic>Neisseria<\/ns4:italic>\n                    species, were obtained from PubMLST and GenBank. Sequence alignments of genes from the meningococcal\n                    <ns4:italic>cps<\/ns4:italic>\n                    , and predicted orthologues in other species, were analysed using Neighbor-nets, BOOTSCANing and maximum likelihood phylogenies.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    The meningococcal\n                    <ns4:italic>cps<\/ns4:italic>\n                    was highly mosaic within regions B, C and D. A subset of sequences within regions B and C were phylogenetically nested within homologous sequences belonging to\n                    <ns4:italic>N. subflava<\/ns4:italic>\n                    , consistent with HGT event in which\n                    <ns4:italic>N. subflava<\/ns4:italic>\n                    was the donor. In the\n                    <ns4:italic>cps<\/ns4:italic>\n                    of 23\/39 isolates, the two copies of region D were highly divergent, with\n                    <ns4:italic>rfbABC\u2019<\/ns4:italic>\n                    sequences being more closely related to predicted orthologues in the proposed species\n                    <ns4:italic>N. weixii\u00a0<\/ns4:italic>\n                    (GenBank accession number\n                    <ns4:ext-link xmlns:ns3=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns3:href=\"https:\/\/www.ncbi.nlm.nih.gov\/nuccore\/CP023429.1%5d\">CP023429.1<\/ns4:ext-link>\n                    ) than the same genes in\n                    <ns4:italic>Nme<\/ns4:italic>\n                    isolates lacking a capsule. There was also evidence of mosaicism in the\n                    <ns4:italic>rfbABC\u2019<\/ns4:italic>\n                    sequences of the remaining 16 isolates, as well as\n                    <ns4:italic>rfbABC<\/ns4:italic>\n                    from many isolates.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Data are consistent with the\n                    <ns4:italic>en bloc<\/ns4:italic>\n                    acquisition of\n                    <ns4:italic>cps<\/ns4:italic>\n                    in meningococci from\n                    <ns4:italic>N. subflava<\/ns4:italic>\n                    , followed by further recombination events with other\n                    <ns4:italic>Neisseria<\/ns4:italic>\n                    species. Nevertheless, the data cannot refute an alternative model, in which native meningococcal capsule existed prior to undergoing HGT with\n                    <ns4:italic>N. subflava<\/ns4:italic>\n                    and other species. Within-genus recombination events may have given rise to the diversity of meningococcal capsule serogroups.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.15333.2","type":"journal-article","created":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T07:18:15Z","timestamp":1564730295000},"page":"99","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Neisseria meningitidis has acquired sequences within the capsule locus by horizontal genetic transfer"],"prefix":"10.12688","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6301-5064","authenticated-orcid":false,"given":"Marianne E. A.","family":"Clemence","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Odile B.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6321-5138","authenticated-orcid":false,"given":"Martin C. J.","family":"Maiden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2019,8,2]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1378-88","DOI":"10.1056\/NEJM200105033441807","article-title":"Meningococcal disease.","volume":"344","author":"N Rosenstein","year":"2001","journal-title":"N Engl J Med."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"3140-5","DOI":"10.1073\/pnas.95.6.3140","article-title":"Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms.","volume":"95","author":"M Maiden","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"1071-7","DOI":"10.1086\/512084","article-title":"Three cases of invasive meningococcal disease caused by a capsule null locus strain circulating among healthy carriers in Burkina Faso.","volume":"195","author":"H Findlow","year":"2007","journal-title":"J Infect Dis."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s12866-017-0942-5","article-title":"Molecular characterization of invasive capsule null Neisseria meningitidis in South Africa.","volume":"17","author":"K Ganesh","year":"2017","journal-title":"BMC Microbiol."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"2346-53","DOI":"10.1128\/IAI.00293-12","article-title":"Invasive potential of nonencapsulated disease isolates of Neisseria meningitidis.","volume":"80","author":"K Johswich","year":"2012","journal-title":"Infect Immun."},{"key":"ref-6","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012393","article-title":"Pathogenesis of meningococcemia.","volume":"3","author":"M Coureuil","year":"2013","journal-title":"Cold Spring Harb Perspect Med."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"144-66","DOI":"10.1128\/cmr.13.1.144-166.2000","article-title":"Update on meningococcal disease with emphasis on pathogenesis and clinical management.","volume":"13","author":"M Van Deuren","year":"2000","journal-title":"Clin Microbiol Rev."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"566-73","DOI":"10.3201\/eid1904.111799","article-title":"Description and nomenclature of Neisseria meningitidis capsule locus.","volume":"19","author":"O Harrison","year":"2013","journal-title":"Emerg Infect Dis."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"885-96","DOI":"10.1111\/j.1365-2958.1994.tb00367.x","article-title":"Contribution of genes from the capsule gene complex (cps) to lipooligosaccharide biosynthesis and serum resistance in Neisseria meningitidis.","volume":"11","author":"S Hammerschmidt","year":"1994","journal-title":"Mol Microbiol."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"645-51","DOI":"10.1021\/bi00597a013","article-title":"Structural elucidation of the 3-deoxy-D-manno-octulosonic acid containing meningococcal 29-e capsular polysaccharide antigen using carbon-13 nuclear magnetic resonance.","volume":"17","author":"A Bhattacharjee","year":"1978","journal-title":"Biochemistry."},{"key":"ref-11","doi-asserted-by":"crossref","first-page":"2275-81","DOI":"10.1016\/S0021-9258(19)42828-7","article-title":"Determination of the structure and conformation of bacterial polysaccharides by carbon 13 nuclear magnetic resonance. 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.16741.r35816, David S. Stephens, Yih-Ling Tzeng, Division of Infectious Diseases, Emory University, Atlanta, GA, USA, 08 Jul 2019, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-99\/v1#referee-response-35816","order":0,"name":"referee-response-35816","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Marianne Clemence<\/b>; <i>Posted: 26 Jul 2019<\/i>; We are grateful to the reviewers for their thorough analysis and interesting suggestions, and have now directly addressed them in version 2. A point-by-point response to their queries and suggestions follows: On insertion sequences, we did not specifically look for evidence that mobile genetic elements were involved in the HGT events between <i>N. subflava <\/i>and <i>N. meningitidis, <\/i>but none were identified during the annotation of the <i>N. subflava cps <\/i>in (1). Nevertheless, the reviewers raise an interesting point that may be worthy of investigation in future studies. With respect to GC content, <i>N. subflava<\/i> has ~50% GC content across the core genome, the same as <i>N. meningitidis,<\/i> therefore no inferences can be made about GC content in capsule export genes between the two species. As reported in (1), the putative region A of <i>N. subflava<\/i> is relatively low at 36-43%, similar to <i>N. meningitidis, <\/i>and is equivalently low in the majority of putative region A genes described in other non-pathogenic <i>Neisseria <\/i>species in the same study. Similarly, GC content has been reported to be low in the capsule synthesis region of other species (2\u20134). Therefore, whilst this is an interesting phenomenon with respect to the common ancestry of Gram-negative capsules, it cannot directly contribute to the present discussion. This has now been commented on in version 2 (discussion paragraph 4). In version two, we have adjusted introduction paragraph 2 to more accurately reflect current understanding of region D genes. The question of region A remains outstanding. Neither <i>N. subflava <\/i>nor <i>N. weixii<\/i> putative region A sequences, nor indeed any other putative non-pathogenic <i>Neisseria <\/i>putative region A, closely resemble any meningococcal region A. Despite the equivalence in biochemical structure between <i>E. coli <\/i>K1, <i>M. haemolytica <\/i>A2 and <i>M. nonliquefaciens <\/i>and meningococcal serogroup B (5), and the clear homology of the associated sequence regions, sequence identity has not been reported to exceed even 70% (6), yet the recombinant regions discussed in the paper appear to have diverged little from their donors. Therefore, we consider it unlikely, though not impossible, that these have directly donated sequences to the meningococcus. Our neighbour-net analyses and BOOTSCANs did not show any evidence that non- <i>Neisseria <\/i>sequences are found in <i>galE <\/i>or region C, so if they were a donor of region A, we contend that the breakpoints of such an event would lie within region A. The mosaic nature of region D does indicate HGT from an as yet unidentified species may exist, but this would be expected to be a member of the <i>Neisseria <\/i>(Figure 6B). In version two, we have added details (discussion paragraph 7). Our view is that we should be seeking novel <i>Neisseria <\/i>species, or species from closely related genera, to answer these questions. We have corrected the oversight about genus names in version two. We also acknowledge that <i>N. weixii <\/i>is an unlikely donor in paragraph two of the discussion, and in version two have corrected the last paragraph in the results that incorrectly implied that it was. As seen in Figure 2, this species is most closely related to <i>N. animalis<\/i>, which was isolated from a guinea pig (7), which is now discussed in paragraph two of the discussion in version 2. Based on cladistics, <i>N. mucosa, N. subflava<\/i>, <i>N. oralis, N. cinerea, \u2018N. bergeri\u2019, N. lactamica <\/i>and <i>N. polysaccharea <\/i>are equally closely related. We could not find any human-associated matches. Nevertheless, not all known human-associated species belong to a single clade. We will look with interest on any new human-associated <i>Neisseria<\/i> that might be discovered in the future. We have added a diagram of the <i>cnl <\/i>locus to paragraph one, in addition to schematics of the <i>cps <\/i>locus of <i>N. subflava <\/i>and <i>N. weixii <\/i>homologue, which are referred to in version 2 (results paragraph 1, discussion paragraph 5). <u>References<\/u> 1. Clemence MEA, Maiden MCJ, Harrison OB. Characterization of capsule genes in non-pathogenic <i>Neisseria species<\/i>. Microb Genomics. 2018;4(9). 2. Clarke BR, Pearce R, Roberts IS. Genetic organization of the <i>Escherichia coli <\/i>K10 capsule gene cluster: Identification and characterization of two conserved regions in group III capsule gene clusters encoding polysaccharide transport functions. J Bacteriol. 1999;181(7):2279\u201385. 3. Nielsen SM, de Gier C, Dimopoulou C, Gupta V, Hansen LH, N&oslash;rskov-Lauritsen N. The capsule biosynthesis locus of <i>Haemophilus influenzae<\/i> shows conspicuous similarity to the corresponding locus in <i>Haemophilus sputorum<\/i> and may have been recruited from this species by horizontal gene transfer. Microbiology. 2015;161(6):1182\u20138. 4. Ito H. The genetic organization of the capsular polysaccharide biosynthesis region of <i>Actinobacillus pleuropneumoniae<\/i> serotype 14. J Vet Med Sci. 2015;77(5):583\u20136. 5. Willis LM, Whitfield C. Structure, biosynthesis, and function of bacterial capsular polysaccharides synthesized by ABC transporter-dependent pathways. Carbohydr Res. 2013;378:35\u201344. 6. Frosch M, Edwards U, Bousset K, Krausse B, Weisgerber C. Evidence for a common molecular origin of the capsule gene loci in Gram-negative bacteria expressing group II capsular polysaccharides. Mol Microbiol. 1991;5(5):1251\u201363. 7. Berger U. <i>Neisseria animalis<\/i> nov. spec. J Hyg Infect Dis. 1960;147(2):158\u201361.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-99\/v2#referee-comment-3901","order":1,"name":"referee-comment-3901","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16741.r35815, H. Steven Seifert, Department of Microbiology\u2013Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 08 Jul 2019, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-99\/v1#referee-response-35815","order":2,"name":"referee-response-35815","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Marianne Clemence<\/b>; <i>Posted: 26 Jul 2019<\/i>; We thank the reviewer for his comments and interest in the article. In response to comments in the final sentences: we have used the robust rMLST scheme (1) for speciation that does not reveal a sublineage within <i>N. subflava <\/i>(2). Nevertheless, we have tried to avoid asserting weight to either hypothesis by only going so far as to say that data \u201care consistent with\u201d an <i>en bloc <\/i>hypothesis. In version 2, we have now emphasised that these data do not provide proof (discussion paragraph 5) of the <i>en bloc <\/i>model. &nbsp; 1. Jolley KA, Bliss CM, Bennett JS, Bratcher HB, Brehony C, Colles FM, Wimalarathna H, Harrison OB, Sheppard SK, Cody AJ, Maiden MCJ. Ribosomal multilocus sequence typing: universal characterization of bacteria from domain to strain. Microbiology. 2012;158:1005-15 2. Bennet JS, Jolley KA, Earle SG, Corton C, Bentley SD, Parkhill J, Maiden MCJ. &nbsp;A genomic approach to bacterial taxonomy: an examination and proposed reclassification of species within the genus <i>Neisseria<\/i>. Microbiology. 2012;158:1570-80","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-99\/v2#referee-comment-3902","order":3,"name":"referee-comment-3902","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The study was funded by the Wellcome Trust (109025 and 087622). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}