David, S.

Efstratiou, A.

Game, L.

Holden, M.T.

Jones, M.D.

Lamagni, T.

Sriskandan, S.

Turner, C.E.

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PubMed

Claire E. Turner

Theresa Lamagni

Matthew T. G. Holden

Sophia David

Michael D. Jones

Laurence Game

Androulla Efstratiou

Shiranee Sriskandan

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Turner et al. Reply to “Emergence of the Same Successful Clade among Distinct Populations of <italic toggle="yes">emm</italic>89 <named-content content-type="genus-species">Streptococcus pyogenes</named-content> in Multiple Geographic Regions”

Turner, Claire E

Lamagni, Theresa

Holden, Matthew T G

David, Sophia

Jones, Michael D

Game, Laurence

Efstratiou, Androulla

Sriskandan, Shiranee

University of St Andrews Research Portal

Turner et al. Reply to "Emergence of the same successful clade among distinct populations of emm89 Streptococcus pyogenes in multiple geographic regions"

Turner, CE

Lamagni, T

Holden, MT

David, S

Jones, M

Game, L

Efstratiou, A

Sriskandan, S

Spiral - Imperial College Digital Repository

Turner et al. Reply to “Emergence of the Same Successful Cladeamong Distinct Populations of emm89 Streptococcus pyogenes inMultiple Geographic Regions”Claire E. Turner,a Theresa Lamagni,b Matthew T. G. Holden,c,d Sophia David,c Michael D. Jones,a,e Laurence Game,eAndroulla Efstratiou,b Shiranee SriskandanaInfectious Diseases & Immunity, Department of Medicine, Imperial College London, London, United Kingdoma; Public Health England, London, United Kingdomb;Pathogen Genomics, The Wellcome Trust Sanger Institute, Cambridge, United Kingdomc; School of Medicine, University of St. Andrews, St. Andrews, United Kingdomd;MRC Clinical Sciences Centre, Hammersmith Hospital, London, United KingdomeWe are pleased that Friães et al. have elected to examineemm89 strains in Portugal (1); it was our hope that othergroups would evaluate emm89 strains from elsewhere, using eitherwhole-genome sequencing (WGS) or the PCR method that wedescribed in our report (2). Subsequent to our publication (2),Zhu et al. used WGS to identify variants of the nga-slo promoteramong emm89 isolates in the United States, Finland, and Iceland(3) indicative of the new emergent emm89 clade in these coun-tries. Although they did not use WGS, Friães et al. demonstratedthat it is likely that the emergent emm89 clade that we identified inthe United Kingdom and elsewhere is also present in Portugal (1).Friães and colleagues have noted that the focus on differentaspects of emm89 strains in the various studies (2–4) makes it hardto determine if the same clade had disseminated in different re-gions. In our original report, we aimed to provide a single com-prehensive description of all six regions of recombination thatcharacterize this emergent emm89 clade (2). Two of these regions,the nga-slo locus (region 2) and the hasABC capsule locus (region6), were highlighted because of their phenotypic significance; itwas beyond the scope of our paper to undertake in-depth analysisof all of the regions. We did, however, clearly demonstrate en-hanced NGA-SLO toxin expression and stated that this could bedue to a single polymorphism or several polymorphisms withinthe nga-slo locus and promoter or elsewhere in the genome. In-deed, it may be misleading to focus on a single region or multipleregions of recombination without understanding of the collectiveimpact of all of the changes. In our sampling of the emm89 pop-ulation, we failed to identify isolates with an intermediate numberof recombination regions, raising the possibility that all six re-modeled regions promoted the success of this lineage, not simplythe two that have been highlighted.To more clearly illustrate the emergence of the new emm89clade, we combined WGS data from isolates from the UnitedStates, Finland, and Iceland reported by Zhu et al. (3) for which wecould confidently determine the sequence type (ST) (n  737)with our data for United Kingdom and Swiss strains (2) (n  131).We identified three distinct lineages (Fig. 1A) that are linked to thethree previously identified nga-slo promoter variants (3). In agree-ment with Friães et al., the original United Kingdom emm89 pop-ulation lineage (with nga-slo promoter “variant 2”) and the emer-gent acapsular emm89 clade (with nga-slo promoter “variant 3”)are both predominantly ST101; any ST variants within this cladeare limited to single-locus variants. Isolates from Finland and Ice-land, with a few minor exceptions, clustered either with the orig-inal United Kingdom emm89 ST101 lineage or with the new emer-gent ST101 clade described in our original paper (2). The majorityof isolates from the United States, however, clustered either withthe third identified lineage (with nga-slo promoter “variant 1”),dominated by ST407 and ST803, or with the new emergent ST101clade. It appears that, as in our original findings in the UnitedKingdom, prior to 2007 to 2008, the dominant emm89 lineage inEuropean countries was an ST101-like lineage but that the domi-nant lineage in the United States was an ST407/ST803-like lineage.Since 2007 to 2008, the new emergent variant, highly likely to havearisen within the ST101 background through recombination, hasrisen to dominance in both Europe and the United States. Allmembers of this emergent clade have the same six regions of re-combination, of which the nga-slo and hasABC regions are justtwo.The ST407/ST803-like lineage sequenced by Zhu et al. (3) wasinfrequent in European countries and is separated from the twoST101-like lineages by a high level of core single nucleotide poly-morphisms (SNPs) (Fig. 1A). In comparison to the emm89 H293reference (ST101), this lineage contains its own distinct predictedpattern of recombination (Fig. 1B). Given the level of differencebetween ST101 and ST407/ST803, the success of the ST101 emer-gent clade in both North America and Europe may therefore re-flect a more general competitive advantage of this new lineage.The findings also highlight a propensity of the genetic backgroundof emm89 to undergo recombination.We agree that the emergent clade has most likely acquired acompetitive advantage through enhanced transmission and/or apropensity for superficial infections. In 2009, a year when the in-cidence of emm89 invasive infections peaked in the United King-dom (2), emm89 accounted for 16% of all 135 noninvasive Strep-tococcus pyogenes isolates submitted in April to November to ourclinical laboratory (which serves a population of approximately 2million) and 13% of 125 invasive S. pyogenes isolates submitted inJanuary to November within London to the national referencelaboratory. This contrasted with emm1 strains, where a dispropor-tionately high number accounted for invasive isolates (23%) com-pared with noninvasive isolates (11%) during the same time peri-Published 1 December 2015Citation Turner CE, Lamagni T, Holden MTG, David S, Jones MD, Game L, Efstratiou A,Sriskandan S. 2015. Turner et al. Reply to “Emergence of the same successful cladeamong distinct populations of emm89 Streptococcus pyogenes in multiple geographicregions.” mBio 6(6):e01883-15. doi:10.1128/mBio.01883-15.Copyright © 2015 Turner et al. This is an open-access article distributed under the termsof the Creative Commons Attribution 3.0 Unported license.Address correspondence to Claire E. Turner, claire.turner01@imperial.ac.uk, or ShiraneeSriskandan, s.sriskandan@imperial.ac.uk.AUTHOR REPLY crossmarkNovember/December 2015 Volume 6 Issue 6 e01883-15 ® mbio.asm.org 1 mbio.asm.org on December 7, 2015 - Published by mbio.asm.orgDownloaded from ods (unpublished data). At present, there are no experimentaldata that directly compare the invasiveness of the emergent cladewith that of previous emm89 lineages. Using population-basedmortality data, we found no evidence that the emergent emm89 clade,where associated with invasive infection, caused greater mortalitythan the original ST101 lineage in the United Kingdom (2).The potential for certain lineages of S. pyogenes to undergoextensive recombination is of wider significance. It seems likelythat future vaccines and/or diagnostic tests will target genes andgene products thought to be crucial for pathogenesis, and yet wehave demonstrated that, at least in emm89, some factors can belost or dramatically altered. The mechanisms explaining why andFIG 1 Phylogenetic analysis of emm89 population. (A) Three lineages were identified in the emm89 population based on the maximum likelihood phylogenyof SNPs identified after mapping to the H293 reference strain of the sequences of 868 emm89 strains from both the United Kingdom study (2) and the UnitedStates/Finland/Iceland study (3), where ST could be confidently assigned. We identified 16 sequence types (ST101, n  621; ST407, n  160; ST580, n  3; ST791,n  2; ST792 to ST800, n  1 each; ST801, n  20; ST802, n  1; ST803, n  52). Two lineages were equivalent to those in the United Kingdom study (2) whichidentified an emergent clade type (red) from a previous lineage (blue) where the major ST was ST101 with some single-locus variants (identified in parentheses).These lineages are also associated with the previously termed capsular nga-slo promoter “variant 2” strains (blue) and acapsular nga-slo promoter “variant 3”strains (red). A third lineage (black) was also identified, representing ST407 and ST803 and two other sequence type variants (ST795 and ST799), equivalent tothe previously termed capsular nga-slo promoter “variant 1” strains. (B) Regions of recombination in a subset of 68 strains representing all of the sequence typesidentified compared to the reference strain H293 (ST101) were predicted using Gubbins (5). Branch colors represent lineages and sequence types. Emergentvariant ST101 (red) and other single-locus variants (indicated with an asterisk [*]) are shown in the following order from the top of the tree: ST791 (maroon),ST802 (orange), ST796 (yellow), ST801 (pink), ST798 (dark red), ST792 (purple), ST580 (green), ST793 (lilac), ST794 (grey-purple), ST800 (bright pink).Previously dominant “European” variant ST101 (blue) and single-locus variant ST797 (pale blue) are shown, as are previously dominant “United States” variantsST407 (black) and ST803 (grey) and single-locus variants ST799 (pale grey) and ST795 (brown). Regions of recombination identified in each strain are shownas vertical red lines (indicating recombination on internal nodes) or blue lines (indicating recombination on terminal branches), and genome coordinates aregiven on the bottom line (turquoise). The six previously identified regions of recombination (R1 to R6) were present in the emergent clade strains of ST101 andother single-locus variants within this lineage, along with a variation in the clustered regularly interspaced short palindromic repeat (CRISPR) region (columnC) (2). The United States variant ST407/ST803 lineage had several large regions of predicted recombination compared to the H293 reference strain, including oneregion which encompassed the MLST yqil locus and introduced the sequence type variation.Author Reply2 ® mbio.asm.org November/December 2015 Volume 6 Issue 6 e01883-15 mbio.asm.org on December 7, 2015 - Published by mbio.asm.orgDownloaded from how these strains undergo recombination-related genome re-modeling have not been determined but clearly require recogni-tion and further evaluation.REFERENCES1. Friães A, Machado MP, Pato C, Carriço J, Melo-Cristino J, Ramirez M.2015. Emergence of the same successful clade among distinct populationsof emm89 Streptococcus pyogenes in multiple geographic regions. mBio6:e01780-15. http://dx.doi.org/10.1128/mBio.01780-15.2. Turner CE, Abbott J, Lamagni T, Holden MTG, David S, Jones MD,Game L, Efstratiou A, Sriskandan S. 2015. Emergence of a new highlysuccessful acapsular group A Streptococcus clade of genotype emm89 in theUnited Kingdom. mBio 6:e00622-15. http://dx.doi.org/10.1128/mBio.00622-15.3. Zhu L, Olsen RJ, Nasser W, Beres SB, Vuopio J, Kristinsson KG,Gottfredsson M, Porter AR, DeLeo FR, Musser JM. 2015. A moleculartrigger for intercontinental epidemics of group A Streptococcus. J Clin Invest125:3545–3559. http://dx.doi.org/10.1172/JCI82478.4. Zhu L, Olsen RJ, Nasser W, de la Riva Morales I, Musser JM. 2015.Trading capsule for increased cytotoxin production: contribution to viru-lence of a newly emerged clade of emm89 Streptococcus pyogenes. mBio6:e01378 –15. http://dx.doi.org/10.1128/mBio.01378-15.5. Croucher NJ, Page AJ, Connor TR, Delaney AJ, Keane JA, Bentley SD,Parkhill J, Harris SR. 2015. Rapid phylogenetic analysis of large samples ofrecombinant bacterial whole genome sequences using Gubbins. NucleicAcids Res 43:e15. http://dx.doi.org/10.1093/nar/gku1196.Author ReplyNovember/December 2015 Volume 6 Issue 6 e01883-15 ® mbio.asm.org 3 mbio.asm.org on December 7, 2015 - Published by mbio.asm.orgDownloaded from 

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Turner et al. Reply to “Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions”

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Turner et al. Reply to “Emergence of the Same Successful Clade among Distinct Populations of
 emm
 89 Streptococcus pyogenes in Multiple Geographic Regions”

University of St. Andrews - Pure

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Turner et al. Reply to “Emergence of the Same Successful Cladeamong Distinct Populations of emm89 Streptococcus pyogenes inMultiple Geographic Regions”Claire E. Turner,a Theresa Lamagni,b Matthew T. G. Holden,c,d Sophia David,c Michael D. Jones,a,e Laurence Game,eAndroulla Efstratiou,b Shiranee SriskandanaInfectious Diseases & Immunity, Department of Medicine, Imperial College London, London, United Kingdoma; Public Health England, London, United Kingdomb;Pathogen Genomics, The Wellcome Trust Sanger Institute, Cambridge, United Kingdomc; School of Medicine, University of St. Andrews, St. Andrews, United Kingdomd;MRC Clinical Sciences Centre, Hammersmith Hospital, London, United KingdomeWe are pleased that Friães et al. have elected to examineemm89 strains in Portugal (1); it was our hope that othergroups would evaluate emm89 strains from elsewhere, using eitherwhole-genome sequencing (WGS) or the PCR method that wedescribed in our report (2). Subsequent to our publication (2),Zhu et al. used WGS to identify variants of the nga-slo promoteramong emm89 isolates in the United States, Finland, and Iceland(3) indicative of the new emergent emm89 clade in these coun-tries. Although they did not use WGS, Friães et al. demonstratedthat it is likely that the emergent emm89 clade that we identified inthe United Kingdom and elsewhere is also present in Portugal (1).Friães and colleagues have noted that the focus on differentaspects of emm89 strains in the various studies (2–4) makes it hardto determine if the same clade had disseminated in different re-gions. In our original report, we aimed to provide a single com-prehensive description of all six regions of recombination thatcharacterize this emergent emm89 clade (2). Two of these regions,the nga-slo locus (region 2) and the hasABC capsule locus (region6), were highlighted because of their phenotypic significance; itwas beyond the scope of our paper to undertake in-depth analysisof all of the regions. We did, however, clearly demonstrate en-hanced NGA-SLO toxin expression and stated that this could bedue to a single polymorphism or several polymorphisms withinthe nga-slo locus and promoter or elsewhere in the genome. In-deed, it may be misleading to focus on a single region or multipleregions of recombination without understanding of the collectiveimpact of all of the changes. In our sampling of the emm89 pop-ulation, we failed to identify isolates with an intermediate numberof recombination regions, raising the possibility that all six re-modeled regions promoted the success of this lineage, not simplythe two that have been highlighted.To more clearly illustrate the emergence of the new emm89clade, we combined WGS data from isolates from the UnitedStates, Finland, and Iceland reported by Zhu et al. (3) for which wecould confidently determine the sequence type (ST) (n  737)with our data for United Kingdom and Swiss strains (2) (n 131).We identified three distinct lineages (Fig. 1A) that are linked to thethree previously identified nga-slopromoter variants (3). In agree-ment with Friães et al., the original United Kingdom emm89 pop-ulation lineage (with nga-slo promoter “variant 2”) and the emer-gent acapsular emm89 clade (with nga-slo promoter “variant 3”)are both predominantly ST101; any ST variants within this cladeare limited to single-locus variants. Isolates from Finland and Ice-land, with a few minor exceptions, clustered either with the orig-inal United Kingdom emm89 ST101 lineage or with the new emer-gent ST101 clade described in our original paper (2). The majorityof isolates from the United States, however, clustered either withthe third identified lineage (with nga-slo promoter “variant 1”),dominated by ST407 and ST803, or with the new emergent ST101clade. It appears that, as in our original findings in the UnitedKingdom, prior to 2007 to 2008, the dominant emm89 lineage inEuropean countries was an ST101-like lineage but that the domi-nant lineage in the United States was an ST407/ST803-like lineage.Since 2007 to 2008, the new emergent variant, highly likely to havearisen within the ST101 background through recombination, hasrisen to dominance in both Europe and the United States. Allmembers of this emergent clade have the same six regions of re-combination, of which the nga-slo and hasABC regions are justtwo.The ST407/ST803-like lineage sequenced by Zhu et al. (3) wasinfrequent in European countries and is separated from the twoST101-like lineages by a high level of core single nucleotide poly-morphisms (SNPs) (Fig. 1A). In comparison to the emm89 H293reference (ST101), this lineage contains its own distinct predictedpattern of recombination (Fig. 1B). Given the level of differencebetween ST101 and ST407/ST803, the success of the ST101 emer-gent clade in both North America and Europe may therefore re-flect a more general competitive advantage of this new lineage.The findings also highlight a propensity of the genetic backgroundof emm89 to undergo recombination.We agree that the emergent clade has most likely acquired acompetitive advantage through enhanced transmission and/or apropensity for superficial infections. In 2009, a year when the in-cidence of emm89 invasive infections peaked in the United King-dom (2), emm89 accounted for 16% of all 135 noninvasive Strep-tococcus pyogenes isolates submitted in April to November to ourclinical laboratory (which serves a population of approximately 2million) and 13% of 125 invasive S. pyogenes isolates submitted inJanuary to November within London to the national referencelaboratory. This contrasted with emm1 strains, where a dispropor-tionately high number accounted for invasive isolates (23%) com-pared with noninvasive isolates (11%) during the same time peri-Published 1 December 2015Citation Turner CE, Lamagni T, Holden MTG, David S, Jones MD, Game L, Efstratiou A,Sriskandan S. 2015. Turner et al. Reply to “Emergence of the same successful cladeamong distinct populations of emm89 Streptococcus pyogenes in multiple geographicregions.” mBio 6(6):e01883-15. doi:10.1128/mBio.01883-15.Copyright © 2015 Turner et al. This is an open-access article distributed under the termsof the Creative Commons Attribution 3.0 Unported license.Address correspondence to Claire E. Turner, claire.turner01@imperial.ac.uk, or ShiraneeSriskandan, s.sriskandan@imperial.ac.uk.AUTHOR REPLY crossmarkNovember/December 2015 Volume 6 Issue 6 e01883-15 ® mbio.asm.org 1 mbio.asm.org on December 3, 2015 - Published by mbio.asm.orgDownloaded from ods (unpublished data). At present, there are no experimentaldata that directly compare the invasiveness of the emergent cladewith that of previous emm89 lineages. Using population-basedmortality data, we found no evidence that the emergent emm89 clade,where associated with invasive infection, caused greater mortalitythan the original ST101 lineage in the United Kingdom (2).The potential for certain lineages of S. pyogenes to undergoextensive recombination is of wider significance. It seems likelythat future vaccines and/or diagnostic tests will target genes andgene products thought to be crucial for pathogenesis, and yet wehave demonstrated that, at least in emm89, some factors can belost or dramatically altered. The mechanisms explaining why andFIG 1 Phylogenetic analysis of emm89 population. (A) Three lineages were identified in the emm89 population based on the maximum likelihood phylogenyof SNPs identified after mapping to the H293 reference strain of the sequences of 868 emm89 strains from both the United Kingdom study (2) and the UnitedStates/Finland/Iceland study (3), where ST could be confidently assigned. We identified 16 sequence types (ST101, n 621; ST407, n 160; ST580, n 3; ST791,n 2; ST792 to ST800, n 1 each; ST801, n 20; ST802, n 1; ST803, n 52). Two lineages were equivalent to those in the United Kingdom study (2) whichidentified an emergent clade type (red) from a previous lineage (blue) where the major ST was ST101 with some single-locus variants (identified in parentheses).These lineages are also associated with the previously termed capsular nga-slo promoter “variant 2” strains (blue) and acapsular nga-slo promoter “variant 3”strains (red). A third lineage (black) was also identified, representing ST407 and ST803 and two other sequence type variants (ST795 and ST799), equivalent tothe previously termed capsular nga-slo promoter “variant 1” strains. (B) Regions of recombination in a subset of 68 strains representing all of the sequence typesidentified compared to the reference strain H293 (ST101) were predicted using Gubbins (5). Branch colors represent lineages and sequence types. Emergentvariant ST101 (red) and other single-locus variants (indicated with an asterisk [*]) are shown in the following order from the top of the tree: ST791 (maroon),ST802 (orange), ST796 (yellow), ST801 (pink), ST798 (dark red), ST792 (purple), ST580 (green), ST793 (lilac), ST794 (grey-purple), ST800 (bright pink).Previously dominant “European” variant ST101 (blue) and single-locus variant ST797 (pale blue) are shown, as are previously dominant “United States” variantsST407 (black) and ST803 (grey) and single-locus variants ST799 (pale grey) and ST795 (brown). Regions of recombination identified in each strain are shownas vertical red lines (indicating recombination on internal nodes) or blue lines (indicating recombination on terminal branches), and genome coordinates aregiven on the bottom line (turquoise). The six previously identified regions of recombination (R1 to R6) were present in the emergent clade strains of ST101 andother single-locus variants within this lineage, along with a variation in the clustered regularly interspaced short palindromic repeat (CRISPR) region (columnC) (2). The United States variant ST407/ST803 lineage had several large regions of predicted recombination compared to the H293 reference strain, including oneregion which encompassed the MLST yqil locus and introduced the sequence type variation.Author Reply2 ® mbio.asm.org November/December 2015 Volume 6 Issue 6 e01883-15 mbio.asm.org on December 3, 2015 - Published by mbio.asm.orgDownloaded from how these strains undergo recombination-related genome re-modeling have not been determined but clearly require recogni-tion and further evaluation.REFERENCES1. Friães A, Machado MP, Pato C, Carriço J, Melo-Cristino J, Ramirez M.2015. Emergence of the same successful clade among distinct populationsof emm89 Streptococcus pyogenes in multiple geographic regions. mBio6:e01780-15. http://dx.doi.org/10.1128/mBio.01780-15.2. Turner CE, Abbott J, Lamagni T, Holden MTG, David S, Jones MD,Game L, Efstratiou A, Sriskandan S. 2015. Emergence of a new highlysuccessful acapsular group A Streptococcus clade of genotype emm89 in theUnited Kingdom. mBio 6:e00622-15. http://dx.doi.org/10.1128/mBio.00622-15.3. Zhu L, Olsen RJ, Nasser W, Beres SB, Vuopio J, Kristinsson KG,Gottfredsson M, Porter AR, DeLeo FR, Musser JM. 2015. A moleculartrigger for intercontinental epidemics of group A Streptococcus. J Clin Invest125:3545–3559. http://dx.doi.org/10.1172/JCI82478.4. Zhu L, Olsen RJ, Nasser W, de la Riva Morales I, Musser JM. 2015.Trading capsule for increased cytotoxin production: contribution to viru-lence of a newly emerged clade of emm89 Streptococcus pyogenes. mBio6:e01378 –15. http://dx.doi.org/10.1128/mBio.01378-15.5. Croucher NJ, Page AJ, Connor TR, Delaney AJ, Keane JA, Bentley SD,Parkhill J, Harris SR. 2015. Rapid phylogenetic analysis of large samples ofrecombinant bacterial whole genome sequences using Gubbins. NucleicAcids Res 43:e15. http://dx.doi.org/10.1093/nar/gku1196.Author ReplyNovember/December 2015 Volume 6 Issue 6 e01883-15 ® mbio.asm.org 3 mbio.asm.org on December 3, 2015 - Published by mbio.asm.orgDownloaded from 

A molecular trigger for intercontinental epidemics of group A Streptococcus.

Emergence of a new highly successful acapsular group A Streptococcus clade of genotype emm89 in the United Kingdom. mBio 6:e00622-15. http://dx.doi.org/10.1128/

Emergence of the same successful clade among distinct populations of emm89 Streptococcus pyogenes in multiple geographic regions. mBio

Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins. Nucleic Acids Res 43:e15.

Trading capsule for increased cytotoxin production: contribution to virulence of a newly emerged clade of emm89 Streptococcus pyogenes. mBio 6:e01378

Turner et al. Reply to "Emergence of the same successful clade among distinct populations of emm89 Streptococcus pyogenes in multiple geographic regions"

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Turner et al. Reply to "Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions"

Turner et al. Reply to "Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions"

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