The emergence and intercontinental spread of a multidrug-resistant clade of typhoid agent Salmonella enterica serovar Typhi

Abstract

BackgroundMultidrug-resistant typhoid is a global health problem. Previous studies conducted in countries of Asia and Africa have identified a highly clonal, multidrug-resistant lineage of Salmonella enterica serovar Typhi (S Typhi), known as H58. However, little is known about the emergence and geographical spread of the H58 clade. In this study, we have used whole-genome sequencing of a global collection of S Typhi to investigate this highly successful lineage. MethodsWe sequenced the whole-genome sequences of 1832 strains of S Typhi isolated between 1905 and 2013 (HiSeq platform, Illumina, San Diego, CA, USA). The isolates originated from 63 countries in six continents (Asia, Africa, North America, South America, Europe, and Oceania). The genomes of all 1832 S Typhi were mapped to the reference strain CT18 from Vietnam, and all single nucleotide changes were extracted and used to generate a maximum likelihood phylogeny of the whole collection. Transmission routes were also investigated with Bayesian analysis. The genomes were interrogated for the presence of plasmids and antimicrobial resistance genes. Long-read sequencing (PacBio platform, Pacific Biosciences, Menlo Park, CA, USA) was used to confirm the chromosomal location of resistance genes in representative isolates. FindingsPhylogenetic reconstruction showed that the multidrug-resistant lineage H58 emerged approximately 30 years ago and has undergone clonal expansion resulting in a widespread global distribution, involving at least 20 countries across Asia, Africa, and Oceania. The analyses showed numerous transmission pathways by which S Typhi H58 is disseminating to many locations worldwide: our data provide evidence that a multidrug-resistant typhoid epidemic is moving across Eastern and Southern Africa. Comparative genomic analysis revealed that the H58 lineage has a distinct genetic profile. Furthermore, isolates from this lineage frequently carried a composite transposable element encoding multiple antimicrobial resistance determinants, which was found either in IncHI1 plasmids or integrated within the chromosome. InterpretationOur study highlights the urgent need for routine surveillance to detect epidemics and monitor fluctuations in the population structure of S Typhi. These data will facilitate public health measures, such as the effective use of antimicrobial agents and the introduction of vaccine programmes, and in doing so will help to address the significant burden of disease caused by typhoid. FundingVKW, DP, AJP, and GD were funded by the Wellcome Trust (098051). NAF was supported by a Wellcome Trust research fellowship (WT092152MA). NAF and this work were supported by a strategic award from the Wellcome Trust for the Malawi-Liverpool Wellcome Trust Clinical Research Programme (101113/Z/13/Z). KEH was supported by the National Health and Medical Research Council of Australia (fellowship 1061409) and the Victorian Life Sciences Computation Initiative (grant VR0082). SB is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (100087/Z/12/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract.