{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T02:13:58Z","timestamp":1772072038436,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011009","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI134727"],"award-info":[{"award-number":["R01AI134727"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI007637"],"award-info":[{"award-number":["T32AI007637"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ISDIN Laboratories"},{"DOI":"10.13039\/100009022","name":"Newcrest Mining","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>In yaws-endemic areas, two-thirds of exudative cutaneous ulcers (CU) are associated with <jats:italic>Treponema pallidum<\/jats:italic> subsp. <jats:italic>pertenue<\/jats:italic> (TP) and <jats:italic>Haemophilus ducreyi<\/jats:italic> (HD); one-third are classified as idiopathic ulcers (IU). A yaws eradication campaign on Lihir Island in Papua New Guinea utilizing mass drug administration (MDA) of azithromycin initially reduced but failed to eradicate yaws; IU rates remained constant throughout the study. Using 16S rRNA gene sequencing, we previously determined that <jats:italic>Streptococcus pyogenes<\/jats:italic> was associated with some cases of IU. Here, we applied shotgun metagenomics to the same samples we analyzed previously by 16S rRNA sequencing to verify this result, identify additional IU-associated microorganisms, and determine why <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic>-associated IU might have persisted after MDA of azithromycin.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p>We sequenced DNA extracted from 244 CU specimens separated into four groups based upon microorganism-specific PCR results (HD+, TP+, TP+HD+, and TP-HD- or IU). <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic> was enriched in IU (24.71% relative abundance [RA]) specimens compared to other ulcer sub-groups, confirming our prior results. We bioinformatically identified the <jats:italic>emm<\/jats:italic> (M protein gene) types found in the <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic> IU specimens and found matches to <jats:italic>emm156 and emm166<\/jats:italic>. Only ~39% of IU specimens contained detectable <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic>, suggesting that additional organisms could be associated with IU. In the sub-set of <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic>-negative IU specimens, <jats:italic>Criibacterium bergeronii<\/jats:italic>, a member of the <jats:italic>Peptostreptococcaceae<\/jats:italic>, and <jats:italic>Fusobacterium necrophorum<\/jats:italic> (7.07% versus 0.00% RA and 2.18% versus 0.00% RA, respectively), were enriched compared to the <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic>-positive sub-set. Although a broad range of viruses were detected in the CU specimens, none were specifically associated with IU.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/Significance<\/jats:title>\n<jats:p>Our observations confirm the association of <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic> with IU in yaws-endemic areas, and suggest that additional anaerobic bacteria, but not other microorganisms, may be associated with this syndrome. Our results should aid in the design of diagnostic tests and selective therapies for CU.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0011009","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T18:32:27Z","timestamp":1671474747000},"page":"e0011009","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Two Streptococcus pyogenes emm types and several anaerobic bacterial species are associated with idiopathic cutaneous ulcers in children after community-based mass treatment with azithromycin"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-7484","authenticated-orcid":true,"given":"Brad","family":"Griesenauer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Xing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine R.","family":"Fortney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camila","family":"Gonz\u00e1lez-Beiras","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oriol","family":"Mitj\u00e0","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qunfeng","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3435-9911","authenticated-orcid":true,"given":"Stanley M.","family":"Spinola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"pntd.0011009.ref001","first-page":"119","article-title":"Epidemiology of yaws: an update.","volume":"6","author":"WM Kazadi","year":"2014","journal-title":"Clinical epidemiology."},{"issue":"4","key":"pntd.0011009.ref002","doi-asserted-by":"crossref","first-page":"e235","DOI":"10.1016\/S2214-109X(14)70019-1","article-title":"Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study","volume":"2","author":"O Mitj\u00e0","year":"2014","journal-title":"The Lancet Global Health"},{"key":"pntd.0011009.ref003","first-page":"22","article-title":"Epidemiology of Haemophilus ducreyi Infections","author":"C Gonzalez-Beiras","year":"2016","journal-title":"Emerging infectious diseases"},{"issue":"3","key":"pntd.0011009.ref004","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1093\/cid\/ciy502","article-title":"Etiological Characterization of the Cutaneous Ulcer Syndrome in Papua New Guinea Using Shotgun Metagenomics","volume":"68","author":"M Noguera-Julian","year":"2018","journal-title":"Clinical Infectious Diseases"},{"issue":"1","key":"pntd.0011009.ref005","doi-asserted-by":"crossref","first-page":"e03162","DOI":"10.1128\/mBio.03162-20","article-title":"Streptococcus pyogenes Is Associated with Idiopathic Cutaneous Ulcers in Children on a Yaws-Endemic Island.","volume":"12","author":"B Griesenauer","year":"2021","journal-title":"mBio."},{"issue":"6","key":"pntd.0011009.ref006","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1093\/trstmh\/trw032","article-title":"Yaws: towards the WHO eradication target","volume":"110","author":"M. 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