Article | Published:

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events

Nature Genetics volume 47, pages 632639 (2015) | Download Citation



The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

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This work was supported by the Wellcome Trust. We would like to thank the members of the Pathogen Informatics Team and the core sequencing teams at the Wellcome Trust Sanger Institute (Cambridge, UK). We are grateful to D. Harris for his superb work in managing the sequence data. We also thank L. Fabre for her excellent technical assistance.

This work was supported by a number of organizations. The authors affiliated with the Wellcome Trust Sanger Institute were funded by Wellcome Trust award 098051; N.A.F. was supported by Wellcome Trust research fellowship WT092152MA. N.A.F., R.S.H. 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). C.M.P. was funded by the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, supported by the Wellcome Trust (Major Overseas Programmes–Thailand Unit Core Grant), the European Society for Paediatric Infectious Diseases and the University of Oxford–Li Ka Shing Global Health Foundation. D.D., P.N. and V.D. were supported by the Wellcome Trust (core grant 089275/H/09/Z). K.E.H. was supported by the National Health and Medical Research Council of Australia (fellowship 1061409) and the Victorian Life Sciences Computation Initiative (VLSCI; grant VR0082). C.A.M. was supported by a Clinical Research Fellowship from GlaxoSmithKline, and P.J.H. was supported by a UK Medical Research Council PhD studentship. This work forms part of a European Union Framework Programme 7 Marie Curie Actions Industry Academia Partnerships and Pathways (IAPP) Consortium Programme, entitled GENDRIVAX (Genome-Driven Vaccine Development for Bacterial Infections), involving the Wellcome Trust Sanger Institute, KEMRI Nairobi and the Novartis Vaccines Institute for Global Health. The authors affiliated with the Institut Pasteur were funded by the Institut Pasteur, the Institut de Veille Sanitaire and the French government 'Investissement d'Avenir' program (Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence, grant ANR-10-LABX-62-IBEID). C.H.W. was supported by the UK Medical Research Council (MR/J003999/1). C.O. was supported by Society in Science and the Branco Weiss Fellowship, administered by ETH Zurich. A.K.C. was supported by the UK Medical Research Council (G1100100/1). J.J. was supported by the antibiotic resistance surveillance project in the Democratic Republic of the Congo, funded by project 2.01 of the Third Framework Agreement between the Belgian Directorate General of Development Cooperation and the Institute of Tropical Medicine (Antwerp, Belgium). F.M. was supported by a research grant from the Bill and Melinda Gates Foundation. The findings and conclusions contained within this publication are those of the authors and do not necessarily reflect positions or policies of the Bill and Melinda Gates Foundation. J.A. Crump was supported by the joint US National Institutes of Health–National Science Foundation Ecology and Evolution of Infectious Disease program (R01 TW009237), the UK Biotechnology and Biological Sciences Research Council (BBSRC; BB/J010367/1) and UK BBSRC Zoonoses in Emerging Livestock Systems awards BB/L017679, BB/L018926 and BB/L018845. S.K. was supported by US National Institutes of Health grant R01 AI099525-02. S.B. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (100087/Z/12/Z). S.O. was supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R01 AI097493). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C.D. was supported by the University of Oxford–Li Ka Shing Global Health Foundation.

Author information

Author notes

    • Kathryn E Holt
    •  & Gordon Dougan

    These authors contributed equally to this work.


  1. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Vanessa K Wong
    • , Derek J Pickard
    • , Julian Parkhill
    • , Andrew J Page
    • , Robert A Kingsley
    • , Nicholas R Thomson
    • , Jacqueline A Keane
    • , Simon R Harris
    • , Alison E Mather
    • , Amy K Cain
    • , James Hadfield
    • , Elizabeth J Klemm
    • , Dafni A Glinos
    • , Samuel Kariuki
    • , Chinyere Okoro
    • , Calman A MacLennan
    •  & Gordon Dougan
  2. Department of Microbiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.

    • Vanessa K Wong
  3. Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

    • Stephen Baker
    • , Nga Tran Vu Thieu
    • , Corinne Thompson
    • , James I Campbell
    • , Guy Thwaites
    • , Duy Pham Thanh
    •  & Jeremy Farrar
  4. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.

    • Stephen Baker
    • , Corinne Thompson
    • , Christiane Dolecek
    • , James I Campbell
    • , Paul Newton
    • , David Dance
    • , Guy Thwaites
    • , Paul Turner
    •  & Jeremy Farrar
  5. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

    • Stephen Baker
    • , Nicholas R Thomson
    •  & E Kim Mulholland
  6. Liverpool School of Tropical Medicine, Liverpool, UK.

    • Nicholas A Feasey
  7. Institute of Food Research, Norwich Research Park, Norwich, UK.

    • Robert A Kingsley
  8. Institut Pasteur, Unité des Bactéries Pathogènes Entériques, Paris, France.

    • François-Xavier Weill
  9. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.

    • David J Edwards
    • , Jane Hawkey
    •  & Kathryn E Holt
  10. Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia.

    • Jane Hawkey
  11. Institute of Biomedical Research, School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK.

    • Peter J Hart
    •  & Calman A MacLennan
  12. Kenya Medical Research Institute (KEMRI), Nairobi, Kenya.

    • Robert F Breiman
    • , Samuel Kariuki
    •  & Robert S Onsare
  13. Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

    • Robert F Breiman
  14. Emory Global Health Institute, Atlanta, Georgia, USA.

    • Robert F Breiman
  15. Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

    • Conall H Watson
    •  & W John Edmunds
  16. Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.

    • Melita A Gordon
  17. Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

    • Robert S Heyderman
    •  & Chisomo Msefula
  18. Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

    • Jan Jacobs
  19. Department of Microbiology and Immunology, Katholieke Universiteit (KU) Leuven, University of Leuven, Leuven, Belgium.

    • Jan Jacobs
  20. National Institute for Biomedical Research, Kinshasa, Democratic Republic of the Congo.

    • Octavie Lunguya
  21. University Hospital of Kinshasa, Kinshasa, Democratic Republic of the Congo.

    • Octavie Lunguya
  22. Microbiology Department, College of Medicine, University of Malawi, Blantyre, Malawi.

    • Chisomo Msefula
  23. Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Montevideo, Uruguay.

    • Jose A Chabalgoity
  24. Ministry of Health, Suva, Fiji.

    • Mike Kama
  25. Fiji Health Sector Support Program, Suva, Fiji.

    • Kylie Jenkins
  26. National Institute of Cholera and Enteric Diseases, Kolkata, India.

    • Shanta Dutta
  27. International Vaccine Institute, Department of Epidemiology, Seoul, Republic of Korea.

    • Florian Marks
  28. Enteropathogen Division, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Carlos G. Malbran Institute, Buenos Aires, Argentina.

    • Josefina Campos
  29. Division of Pediatric Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.

    • Stephen Obaro
  30. University of Abuja Teaching Hospital, Abuja, Nigeria.

    • Stephen Obaro
  31. Bingham University, Karu, Nigeria.

    • Stephen Obaro
  32. Novartis Vaccines Institute for Global Health, Siena, Italy.

    • Calman A MacLennan
  33. Centre for Enteric Diseases, National Institute for Communicable Diseases, Division in the National Health Laboratory Service, University of the Witwatersrand, Johannesburg, South Africa.

    • Karen H Keddy
    •  & Anthony M Smith
  34. Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.

    • Christopher M Parry
  35. Graduate School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.

    • Christopher M Parry
  36. Patan Academy of Health Sciences, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Kathmandu, Nepal.

    • Abhilasha Karkey
    • , Sabina Dongol
    •  & Buddha Basnyat
  37. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.

    • E Kim Mulholland
  38. Enteric and Leptospira Reference Laboratory, Institute of Environmental Science and Research, Ltd. (ESR), Porirua, New Zealand.

    • Muriel Dufour
  39. National Centre for Biosecurity and Infectious Disease, Institute of Environmental Science and Research, Porirua, New Zealand.

    • Don Bandaranayake
  40. Samoa Ministry of Health, Apia, Samoa.

    • Take Toleafoa Naseri
  41. National Influenza Center, World Health Organization, Center for Communicable Disease Control, Suva, Fiji.

    • Shalini Pravin Singh
  42. Department of Microbiology, Hasanuddin University, Makassar, Indonesia.

    • Mochammad Hatta
  43. Lao Oxford Mahosot Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos.

    • Paul Newton
    • , David Dance
    •  & Viengmon Davong
  44. National Health Services, Tupua Tamasese Meaole Hospital, Apia, Samoa.

    • Lupeoletalalei Isaia
  45. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    • Lalith Wijedoru
    •  & Paul Turner
  46. Paediatric Emergency Medicine, Chelsea and Westminster Hospital, London, UK.

    • Lalith Wijedoru
  47. Centre for International Health and Otago International Health Research Network, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

    • John A Crump
  48. Salmonella Reference Service, Public Health England, Colindale, London, UK.

    • Elizabeth De Pinna
    •  & Satheesh Nair
  49. Emerging Disease Surveillance and Response, Division of Pacific Technical Support, World Health Organization, Suva, Fiji.

    • Eric J Nilles
  50. Cambodia-Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.

    • Paul Turner
    •  & Sona Soeng
  51. Microbiological Diagnostic Unit–Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.

    • Mary Valcanis
    • , Joan Powling
    • , Karolina Dimovski
    •  & Geoff Hogg


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Study design: V.K.W., S.B., J. Parkhill , N.R.T., K.E.H. and G.D. Sequencing data generation: A.J.P., J.A.K. and E.J.K. Data analysis: V.K.W., K.E.H., J. Parkhill, N.R.T., A.J.P., J.A.K., D.J.E., J. Hawkey, S.R.H., A.E.M., A.K.C., J. Hadfield, C.O., R.A.K., E.J.K., D.A.G. and D.J.P. Isolate acquisition and processing and clinical data collection: D.J.P., S.B., N.A.F., N.R.T., F.-X.W., P.J.H., N.T.V.T., R.F.B., C.H.W., S.K., M.A.G., R.S.H., J.J., O.L., W.J.E., C.M., J.A. Chabalgoity, M.K., K.J., S. Dutta, F.M., J.C., C.T., S.O., C.A.M., C.D., K.H.K., A.M.S., C.M.P., A.K., E.K.M., J.I.C., S. Dongol, B.B., M.D., D.B., T.T.N., S.P.S., M.H., P.N., R.S.O., L.I., D.D., V.D., G.T., L.W., J.A. Crump, E.D.P., S.N., E.J.N., D.P.T., P.T., S.S., M.V., J. Powling, K.D., G.H., J.F. and K.E.H. Manuscript writing: V.K.W., S.B., K.E.H. and G.D. All authors contributed to manuscript editing. Project oversight: S.B., K.E.H. and G.D.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vanessa K Wong.

Integrated supplementary information

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Tables 2–7.

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    Supplementary Table 1

    Isolates used in the study.

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