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Emergence of a globally dominant IncHI1 plasmid type associated with multiple drug resistant typhoid.

Holt KE, Phan MD, Baker S, Duy PT, Nga TV, Nair S, Turner AK, Walsh C, Fanning S, Farrell-Ward S, Dutta S, Kariuki S, Weill FX, Parkhill J, Dougan G, Wain J - PLoS Negl Trop Dis (2011)

Bottom Line: To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S.Typhi host.The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. kholt@unimelb.edu.au

ABSTRACT
Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a serious global health concern. Since their emergence in the mid-1970s multi-drug resistant (MDR) S. Typhi now dominate drug sensitive equivalents in many regions. MDR in S. Typhi is almost exclusively conferred by self-transmissible IncHI1 plasmids carrying a suite of antimicrobial resistance genes. We identified over 300 single nucleotide polymorphisms (SNPs) within conserved regions of the IncHI1 plasmid, and genotyped both plasmid and chromosomal SNPs in over 450 S. Typhi dating back to 1958. Prior to 1995, a variety of IncHI1 plasmid types were detected in distinct S. Typhi haplotypes. Highly similar plasmids were detected in co-circulating S. Typhi haplotypes, indicative of plasmid transfer. In contrast, from 1995 onwards, 98% of MDR S. Typhi were plasmid sequence type 6 (PST6) and S. Typhi haplotype H58, indicating recent global spread of a dominant MDR clone. To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S. Typhi host. The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU.

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Phylogenetic tree of the H58 haplogroup of S. Typhi.Dashed line indicates where this tree joins into the larger phylogenetic tree of S. Typhi (shown in Figure 3A). The two major H58 lineages are indicated by colour (blue, lineage I; red, lineage II; purple, common ancestor of both lineages). Nodes are labelled with isolate names (outer nodes representing sequenced isolates; see [45]), haplotype (H followed by number, as defined in [41]) or letters indicating nodes resolved by SNP typing. Node sizes indicate the relative frequency of each haplotype within the study collection of 269 H58 S. Typhi isolates, according to the scale provided. The proportion of isolates in each node carrying the PST6 plasmid and IS1 (solid colour), IS1 only (white) or neither (grey) is indicated by shading.
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pntd-0001245-g004: Phylogenetic tree of the H58 haplogroup of S. Typhi.Dashed line indicates where this tree joins into the larger phylogenetic tree of S. Typhi (shown in Figure 3A). The two major H58 lineages are indicated by colour (blue, lineage I; red, lineage II; purple, common ancestor of both lineages). Nodes are labelled with isolate names (outer nodes representing sequenced isolates; see [45]), haplotype (H followed by number, as defined in [41]) or letters indicating nodes resolved by SNP typing. Node sizes indicate the relative frequency of each haplotype within the study collection of 269 H58 S. Typhi isolates, according to the scale provided. The proportion of isolates in each node carrying the PST6 plasmid and IS1 (solid colour), IS1 only (white) or neither (grey) is indicated by shading.

Mentions: The clonal expansion of H58 S. Typhi has been documented previously [22], [41], however the role of the PST6 plasmid has not been investigated. Among our collection, the oldest S. Typhi H58 isolate dates back to 1995 and carries the PST6 plasmid. To ascertain whether the common ancestor of S. Typhi H58 might have carried the PST6 plasmid, the phylogenetic structure among our 293 S. Typhi H58 isolates was resolved using 45 of the assayed SNP loci that differentiate within the H58 haplogroup (Figure 4). These SNPs divided the isolates into 24 distinct H58 haplotypes, with the majority (N = 270) in 13 haplotypes (Figure 4). Most of the H58 haplotypes (N = 14), including the ancestral haplotype A, included isolates harbouring the PST6 plasmid (Figure 4). We have previously sequenced the genomes of 19 S. Typhi, including seven isolates from the H58 haplogroup [45], and observed the insertion of an IS1 transposase between protein coding sequences STY3618 and STY3619 within all sequenced H58 S. Typhi genomes. This transposase was identical at the nucleotide level to the IS1 sequences within Tn9 in IncHI1 plasmids pHCM1 and pAKU_1, and shared a common insertion site in all seven S. Typhi H58 chromosomes sequenced [45]. In the present study, our SNP assays included a probe targeting sequences within the IS1 gene (SPAP0007). Nearly all of the S. Typhi H58 isolates gave positive signals for this IS1 target (Figure 4; coloured or white), with the sole exception of six isolates belonging to the H58 ancestral haplotype A (Figure 4, grey), which also included three isolates that carried the PST6 plasmid and tested positive for IS1 (Figure 4, purple). This suggests that the PST6 plasmid was likely acquired by the most recent common ancestor of S. Typhi H58 (Figure 4, haplotype A), followed by transposition of IS1 into the S. Typhi chromosome prior to divergence into subtypes of H58. Thus the dominance of PST6 over other MDR IncHI1 plasmids (noted here and previously [37]) and the dominance of H58 over other S. Typhi haplotypes (noted here and previously [22], [41]) appears to be the result of a trans-continental clonal expansion of MDR S. Typhi H58 carrying the PST6 plasmid.


Emergence of a globally dominant IncHI1 plasmid type associated with multiple drug resistant typhoid.

Holt KE, Phan MD, Baker S, Duy PT, Nga TV, Nair S, Turner AK, Walsh C, Fanning S, Farrell-Ward S, Dutta S, Kariuki S, Weill FX, Parkhill J, Dougan G, Wain J - PLoS Negl Trop Dis (2011)

Phylogenetic tree of the H58 haplogroup of S. Typhi.Dashed line indicates where this tree joins into the larger phylogenetic tree of S. Typhi (shown in Figure 3A). The two major H58 lineages are indicated by colour (blue, lineage I; red, lineage II; purple, common ancestor of both lineages). Nodes are labelled with isolate names (outer nodes representing sequenced isolates; see [45]), haplotype (H followed by number, as defined in [41]) or letters indicating nodes resolved by SNP typing. Node sizes indicate the relative frequency of each haplotype within the study collection of 269 H58 S. Typhi isolates, according to the scale provided. The proportion of isolates in each node carrying the PST6 plasmid and IS1 (solid colour), IS1 only (white) or neither (grey) is indicated by shading.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3139670&req=5

pntd-0001245-g004: Phylogenetic tree of the H58 haplogroup of S. Typhi.Dashed line indicates where this tree joins into the larger phylogenetic tree of S. Typhi (shown in Figure 3A). The two major H58 lineages are indicated by colour (blue, lineage I; red, lineage II; purple, common ancestor of both lineages). Nodes are labelled with isolate names (outer nodes representing sequenced isolates; see [45]), haplotype (H followed by number, as defined in [41]) or letters indicating nodes resolved by SNP typing. Node sizes indicate the relative frequency of each haplotype within the study collection of 269 H58 S. Typhi isolates, according to the scale provided. The proportion of isolates in each node carrying the PST6 plasmid and IS1 (solid colour), IS1 only (white) or neither (grey) is indicated by shading.
Mentions: The clonal expansion of H58 S. Typhi has been documented previously [22], [41], however the role of the PST6 plasmid has not been investigated. Among our collection, the oldest S. Typhi H58 isolate dates back to 1995 and carries the PST6 plasmid. To ascertain whether the common ancestor of S. Typhi H58 might have carried the PST6 plasmid, the phylogenetic structure among our 293 S. Typhi H58 isolates was resolved using 45 of the assayed SNP loci that differentiate within the H58 haplogroup (Figure 4). These SNPs divided the isolates into 24 distinct H58 haplotypes, with the majority (N = 270) in 13 haplotypes (Figure 4). Most of the H58 haplotypes (N = 14), including the ancestral haplotype A, included isolates harbouring the PST6 plasmid (Figure 4). We have previously sequenced the genomes of 19 S. Typhi, including seven isolates from the H58 haplogroup [45], and observed the insertion of an IS1 transposase between protein coding sequences STY3618 and STY3619 within all sequenced H58 S. Typhi genomes. This transposase was identical at the nucleotide level to the IS1 sequences within Tn9 in IncHI1 plasmids pHCM1 and pAKU_1, and shared a common insertion site in all seven S. Typhi H58 chromosomes sequenced [45]. In the present study, our SNP assays included a probe targeting sequences within the IS1 gene (SPAP0007). Nearly all of the S. Typhi H58 isolates gave positive signals for this IS1 target (Figure 4; coloured or white), with the sole exception of six isolates belonging to the H58 ancestral haplotype A (Figure 4, grey), which also included three isolates that carried the PST6 plasmid and tested positive for IS1 (Figure 4, purple). This suggests that the PST6 plasmid was likely acquired by the most recent common ancestor of S. Typhi H58 (Figure 4, haplotype A), followed by transposition of IS1 into the S. Typhi chromosome prior to divergence into subtypes of H58. Thus the dominance of PST6 over other MDR IncHI1 plasmids (noted here and previously [37]) and the dominance of H58 over other S. Typhi haplotypes (noted here and previously [22], [41]) appears to be the result of a trans-continental clonal expansion of MDR S. Typhi H58 carrying the PST6 plasmid.

Bottom Line: To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S.Typhi host.The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. kholt@unimelb.edu.au

ABSTRACT
Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a serious global health concern. Since their emergence in the mid-1970s multi-drug resistant (MDR) S. Typhi now dominate drug sensitive equivalents in many regions. MDR in S. Typhi is almost exclusively conferred by self-transmissible IncHI1 plasmids carrying a suite of antimicrobial resistance genes. We identified over 300 single nucleotide polymorphisms (SNPs) within conserved regions of the IncHI1 plasmid, and genotyped both plasmid and chromosomal SNPs in over 450 S. Typhi dating back to 1958. Prior to 1995, a variety of IncHI1 plasmid types were detected in distinct S. Typhi haplotypes. Highly similar plasmids were detected in co-circulating S. Typhi haplotypes, indicative of plasmid transfer. In contrast, from 1995 onwards, 98% of MDR S. Typhi were plasmid sequence type 6 (PST6) and S. Typhi haplotype H58, indicating recent global spread of a dominant MDR clone. To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S. Typhi host. The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU.

Show MeSH
Related in: MedlinePlus