{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:40:55Z","timestamp":1790419255030,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T00:00:00Z","timestamp":1556064000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03AI128290"],"award-info":[{"award-number":["R03AI128290"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biomedical Research Excellence","award":["P20GM103440"],"award-info":[{"award-number":["P20GM103440"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Bacterial infections following childbirth\u2014so-called puerperal infections\u2014cause morbidity in 5%\u201310% of all new mothers. At low frequency, the infection can spread to the blood, resulting in life-threatening sepsis known as puerperal sepsis. Pathogens causing puerperal sepsis include group A Streptococcus (GAS), and epidemiological analyses have identified isolates of a single serotype, M28, as being nonrandomly associated with cases of puerperal sepsis. The genomes of serotype M28 GAS isolates harbor a 36.3-kb mobile genetic element of apparent group B Streptococcus origin, termed region of difference 2 (RD2).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The phenotypic (determined via tissue culture and a vaginal colonization model) and regulatory (determined via RNA sequencing analysis) contributions of RD2 were assessed by comparing parental, RD2 deletion mutant, and complemented mutant serotype M28 GAS strains.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>RD2 affords serotype M28 isolates an enhanced ability to adhere to human vaginal epithelial cells and to colonize the female reproductive tract in a mouse model of infection. In addition, RD2 influences the abundance of messenger RNAs from &gt;100 core chromosomal GAS genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The data are consistent with RD2 directly, via encoded virulence factors, and indirectly, via encoded regulatory proteins, modifying the virulence potential of GAS and contributing to the decades-old association of serotype M28 isolates with cases of puerperal sepsis.<\/jats:p><\/jats:sec>","DOI":"10.1093\/infdis\/jiz195","type":"journal-article","created":{"date-parts":[[2019,4,18]],"date-time":"2019-04-18T19:14:22Z","timestamp":1555614862000},"page":"882-891","source":"Crossref","is-referenced-by-count":20,"title":["A Mobile Genetic Element Promotes the Association Between Serotype M28 Group A Streptococcus Isolates and Cases of Puerperal Sepsis"],"prefix":"10.1093","volume":"220","author":[{"given":"Ira","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poulomee","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L","family":"Danger","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josette","family":"Medicielo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshika","family":"Roshika","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Calfee","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama","family":"Ramalinga","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-4159","authenticated-orcid":false,"given":"Paul","family":"Sumby","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada\u2013Reno School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"2019073103402953300_CIT0001","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1086\/338466","article-title":"Severe group a streptococcal soft-tissue infections in Ontario: 1992\u20131996","volume":"34","author":"Sharkawy","year":"2002","journal-title":"Clin Infect Dis"},{"key":"2019073103402953300_CIT0002","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1093\/cid\/cit282","article-title":"Pregnancy-related group a streptococcal infections: temporal relationships between bacterial acquisition, infection onset, clinical findings, and outcome","volume":"57","author":"Hamilton","year":"2013","journal-title":"Clin Infect Dis"},{"key":"2019073103402953300_CIT0003","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1093\/cid\/cir325","article-title":"Incidence and severity of invasive Streptococcus pneumoniae, group A Streptococcus, and group B Streptococcus infections among pregnant and postpartum women","volume":"53","author":"Deutscher","year":"2011","journal-title":"Clin Infect Dis"},{"key":"2019073103402953300_CIT0004","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1600-0897.2011.01083.x","article-title":"Postpartum group a Streptococcus sepsis and maternal immunology","volume":"67","author":"Mason","year":"2012","journal-title":"Am J Reprod Immunol"},{"key":"2019073103402953300_CIT0005","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/S0140-6736(06)68397-9","article-title":"WHO analysis of causes of maternal death: a systematic review","volume":"367","author":"Khan","year":"2006","journal-title":"Lancet"},{"key":"2019073103402953300_CIT0006","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3201\/eid0705.010511","article-title":"Epidemiology of and surveillance for postpartum infections","volume":"7","author":"Yokoe","year":"2001","journal-title":"Emerg Infect Dis"},{"key":"2019073103402953300_CIT0007","doi-asserted-by":"crossref","first-page":"ofy159","DOI":"10.1093\/ofid\/ofy159","article-title":"Postpartum group A streptococcus case series: reach out to infection prevention!","volume":"5","author":"Alexander","year":"2018","journal-title":"Open Forum Infect Dis"},{"key":"2019073103402953300_CIT0008","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1097\/AOG.0b013e31826d60c5","article-title":"Severe maternal morbidity among delivery and postpartum hospitalizations in the United States","volume":"120","author":"Callaghan","year":"2012","journal-title":"Obstet Gynecol"},{"key":"2019073103402953300_CIT0009","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/01.ogx.0000265998.40912.5e","article-title":"Puerperal pyrexia: a review. Part I","volume":"62","author":"Maharaj","year":"2007","journal-title":"Obstet Gynecol Surv"},{"key":"2019073103402953300_CIT0010","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/QCO.0b013e328339257c","article-title":"Maternal sepsis: epidemiology, etiology and outcome","volume":"23","author":"van Dillen","year":"2010","journal-title":"Curr Opin Infect Dis"},{"key":"2019073103402953300_CIT0011","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S1473-3099(09)70178-1","article-title":"Global emm type distribution of group A streptococci: systematic review and implications for vaccine development","volume":"9","author":"Steer","year":"2009","journal-title":"Lancet Infect Dis"},{"key":"2019073103402953300_CIT0012","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1136\/jcp.15.3.231","article-title":"Frequency of serotypes of Streptococcus pyogenes in different diseases","volume":"15","author":"Mitchell","year":"1962","journal-title":"J Clin Pathol"},{"key":"2019073103402953300_CIT0013","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0140-6736(54)90004-5","article-title":"Type-12 streptococci associated with acute haemorrhagic nephritis","volume":"267","author":"Wilmers","year":"1954","journal-title":"Lancet"},{"key":"2019073103402953300_CIT0014","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1099\/00222615-39-3-165","article-title":"The serotypes of Streptococcus pyogenes present in Britain during 1980\u20131990 and their association with disease","volume":"39","author":"Colman","year":"1993","journal-title":"J Med Microbiol"},{"key":"2019073103402953300_CIT0015","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1086\/342062","article-title":"Population-based surveillance for postpartum invasive group a streptococcus infections, 1995\u20132000","volume":"35","author":"Chuang","year":"2002","journal-title":"Clin Infect Dis"},{"key":"2019073103402953300_CIT0016","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jri.2009.06.126","article-title":"Group A streptococcal puerperal sepsis: initial characterization of virulence factors in association with clinical parameters","volume":"82","author":"Byrne","year":"2009","journal-title":"J Reprod Immunol"},{"key":"2019073103402953300_CIT0017","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1086\/519936","article-title":"Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden","volume":"45","author":"Darenberg","year":"2007","journal-title":"Clin Infect Dis"},{"key":"2019073103402953300_CIT0018","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1128\/IAI.01639-13","article-title":"Natural disruption of two regulatory networks in serotype M3 group A Streptococcus isolates contributes to the virulence factor profile of this hypervirulent serotype","volume":"82","author":"Cao","year":"2014","journal-title":"Infect Immun"},{"key":"2019073103402953300_CIT0019","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1086\/430618","article-title":"Genome sequence of a serotype M28 strain of group a streptococcus: potential new insights into puerperal sepsis and bacterial disease specificity","volume":"192","author":"Green","year":"2005","journal-title":"J Infect Dis"},{"key":"2019073103402953300_CIT0020","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1471-2180-11-65","article-title":"Lateral gene transfer of streptococcal ICE element RD2 (region of difference 2) encoding secreted proteins","volume":"11","author":"Sitkiewicz","year":"2011","journal-title":"BMC Microbiol"},{"key":"2019073103402953300_CIT0021","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1111\/cmi.12105","article-title":"Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization","volume":"15","author":"Patras","year":"2013","journal-title":"Cell Microbiol"},{"key":"2019073103402953300_CIT0022","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1093\/infdis\/jix684","article-title":"Diminished capsule exacerbates virulence, blood-brain barrier penetration, intracellular persistence, and antibiotic evasion of hyperhemolytic group B streptococci","volume":"217","author":"Gendrin","year":"2018","journal-title":"J Infect Dis"},{"key":"2019073103402953300_CIT0023","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1371\/journal.ppat.0020005","article-title":"Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity","volume":"2","author":"Sumby","year":"2006","journal-title":"PLoS Pathog"},{"key":"2019073103402953300_CIT0024","doi-asserted-by":"crossref","first-page":"e00792","DOI":"10.1128\/IAI.00792-17","article-title":"Identification and characterization of serotype-specific variation in group A streptococcus pilus expression","volume":"86","author":"Calfee","year":"2018","journal-title":"Infect Immun"},{"key":"2019073103402953300_CIT0025","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1111\/j.1365-2958.2010.07427.x","article-title":"The group A Streptococcus small regulatory RNA FasX enhances streptokinase activity by increasing the stability of the ska mRNA transcript","volume":"78","author":"Ramirez-Pe\u00f1a","year":"2010","journal-title":"Mol Microbiol"},{"key":"2019073103402953300_CIT0026","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1128\/IAI.68.2.535-542.2000","article-title":"Nonpolar inactivation of the hypervariable streptococcal inhibitor of complement gene (sic) in serotype M1 Streptococcus pyogenes significantly decreases mouse mucosal colonization","volume":"68","author":"Lukomski","year":"2000","journal-title":"Infect Immun"},{"key":"2019073103402953300_CIT0027","doi-asserted-by":"crossref","first-page":"26836","DOI":"10.1038\/srep26836","article-title":"Interleukin-17A contributes to the control of Streptococcus pyogenes colonization and inflammation of the female genital tract","volume":"6","author":"Carey","year":"2016","journal-title":"Sci Rep"},{"key":"2019073103402953300_CIT0028","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1128\/IAI.00021-13","article-title":"Murine vaginal colonization model for investigating asymptomatic mucosal carriage of Streptococcus pyogenes","volume":"81","author":"Watson","year":"2013","journal-title":"Infect Immun"},{"key":"2019073103402953300_CIT0029","doi-asserted-by":"crossref","first-page":"e140","DOI":"10.1093\/nar\/gkt444","article-title":"Computational analysis of bacterial RNA-Seq data","volume":"41","author":"McClure","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2019073103402953300_CIT0030","doi-asserted-by":"crossref","first-page":"e00274","DOI":"10.1128\/IAI.00274-17","article-title":"RocA is an accessory protein to the virulence-regulating CovRS two-component system in group A streptococcus","volume":"85","author":"Jain","year":"2017","journal-title":"Infection and immunity"},{"key":"2019073103402953300_CIT0031","doi-asserted-by":"crossref","first-page":"7985","DOI":"10.1073\/pnas.93.15.7985","article-title":"Peptide methionine sulfoxide reductase contributes to the maintenance of adhesins in three major pathogens","volume":"93","author":"Wizemann","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2019073103402953300_CIT0032","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1095\/biolreprod57.4.847","article-title":"Generation of papillomavirus-immortalized cell lines from normal human ectocervical, endocervical, and vaginal epithelium that maintain expression of tissue-specific differentiation proteins","volume":"57","author":"Fichorova","year":"1997","journal-title":"Biol Reprod"},{"key":"2019073103402953300_CIT0033","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1046\/j.1365-2958.1999.01470.x","article-title":"The R28 protein of Streptococcus pyogenes is related to several group B streptococcal surface proteins, confers protective immunity and promotes binding to human epithelial cells","volume":"33","author":"St\u00e5lhammar-Carlemalm","year":"1999","journal-title":"Mol Microbiol"},{"key":"2019073103402953300_CIT0034","doi-asserted-by":"crossref","first-page":"14249","DOI":"10.1073\/pnas.0503838102","article-title":"Small RNA genes expressed from Staphylococcus aureus genomic and pathogenicity islands with specific expression among pathogenic strains","volume":"102","author":"Pichon","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2019073103402953300_CIT0035","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1111\/j.1365-2958.2007.05991.x","article-title":"A small non-coding RNA of the invasion gene island (SPI-1) represses outer membrane protein synthesis from the Salmonella core genome","volume":"66","author":"Pfeiffer","year":"2007","journal-title":"Mol Microbiol"},{"key":"2019073103402953300_CIT0036","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1128\/JB.01449-13","article-title":"Identification of HilD-regulated genes in Salmonella enterica serovar Typhimurium","volume":"196","author":"Petrone","year":"2014","journal-title":"J Bacteriol"},{"key":"2019073103402953300_CIT0037","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1093\/emboj\/20.12.3046","article-title":"EndoS, a novel secreted protein from Streptococcus pyogenes with endoglycosidase activity on human IgG","volume":"20","author":"Collin","year":"2001","journal-title":"EMBO J"},{"key":"2019073103402953300_CIT0038","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1096\/fj.06-5804fje","article-title":"Trigger for group A streptococcal M1T1 invasive disease","volume":"20","author":"Cole","year":"2006","journal-title":"FASEB J"},{"key":"2019073103402953300_CIT0039","doi-asserted-by":"crossref","first-page":"e1003842","DOI":"10.1371\/journal.ppat.1003842","article-title":"RocA truncation underpins hyper-encapsulation, carriage longevity and transmissibility of serotype M18 group A streptococci","volume":"9","author":"Lynskey","year":"2013","journal-title":"PLoS Pathog"},{"key":"2019073103402953300_CIT0040","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/mmi.13136","article-title":"Regulatory rewiring confers serotype-specific hyper-virulence in the human pathogen group A Streptococcus","volume":"98","author":"Miller","year":"2015","journal-title":"Mol Microbiol"},{"key":"2019073103402953300_CIT0041","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1111\/mmi.13584","article-title":"Regulatory gene mutation: a driving force behind group a Streptococcus strain- and serotype-specific variation","volume":"103","author":"Sarkar","year":"2017","journal-title":"Mol Microbiol"},{"key":"2019073103402953300_CIT0042","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1099\/mic.0.000003","article-title":"Shiga toxins and stx phages: highly diverse entities","volume":"161","author":"Kr\u00fcger","year":"2015","journal-title":"Microbiology"},{"key":"2019073103402953300_CIT0043","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/IAI.00872-10","article-title":"Regulatory mechanism for exfoliative toxin production in Staphylococcus aureus","volume":"79","author":"Kato","year":"2011","journal-title":"Infect Immun"},{"key":"2019073103402953300_CIT0044","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s10096-016-2593-0","article-title":"Virulence factors of Streptococcus pyogenes strains from women in peri-labor with invasive infections","volume":"35","author":"Goli\u0144ska","year":"2016","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"2019073103402953300_CIT0045","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1128\/JCM.00675-12","article-title":"Analysis of a Streptococcus pyogenes puerperal sepsis cluster by use of whole-genome sequencing","volume":"50","author":"Ben Zakour","year":"2012","journal-title":"J Clin Microbiol"},{"key":"2019073103402953300_CIT0046","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1128\/JCM.00679-13","article-title":"Molecular analysis of an outbreak of lethal postpartum sepsis caused by Streptococcus pyogenes","volume":"51","author":"Turner","year":"2013","journal-title":"J Clin Microbiol"},{"key":"2019073103402953300_CIT0047","doi-asserted-by":"crossref","first-page":"e62433","DOI":"10.1371\/journal.pone.0062433","article-title":"The AgI\/II family adhesin AspA is required for respiratory infection by Streptococcus pyogenes","volume":"8","author":"Franklin","year":"2013","journal-title":"PLoS One"},{"key":"2019073103402953300_CIT0048","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41588-018-0343-1","article-title":"Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis","volume":"51","author":"Kachroo","year":"2019","journal-title":"Nat Genet"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiz195\/28675849\/jiz195.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/220\/5\/882\/29021596\/jiz195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T08:58:20Z","timestamp":1663318700000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/220\/5\/882\/5478982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,23]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,4,23]]},"published-print":{"date-parts":[[2019,7,31]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiz195","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,9,1]]},"published":{"date-parts":[[2019,4,23]]}}}