Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission

1. Stephen Baker1,2,*,†,
2. Kathryn E. Holt3,4,†,
3. Archie C. A. Clements5,
4. Abhilasha Karkey2,
5. Amit Arjyal2,
6. Maciej F. Boni1,6,
7. Sabina Dongol2,
8. Naomi Hammond4,
9. Samir Koirala2,
10. Pham Thanh Duy1,
11. Tran Vu Thieu Nga1,
12. James I. Campbell1,
13. Christiane Dolecek1,2,
14. Buddha Basnyat2,
15. Gordon Dougan4 and
16. Jeremy J. Farrar1,2

+ Author Affiliations

1. ¹The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, Vietnam
2. ²Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal
3. ³Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia
4. ⁴The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
5. ⁵University of Queensland, School of Population Health, Brisbane, Australia
6. ⁶The MRC Centre for Genomics and Global Health, Oxford, UK

1. ↵Author for correspondence: Stephen Baker e-mail: sbaker@oucru.org

1. ↵† These authors contributed equally to this study.

 

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Abstract

Typhoid is a systemic infection caused by Salmonella Typhi and Salmonella Paratyphi A, human-restricted bacteria that are transmitted faeco-orally. Salmonella Typhi and S. Paratyphi A are clonal, and their limited genetic diversity has precluded the identification of long-term transmission networks in areas with a high disease burden. To improve our understanding of typhoid transmission we have taken a novel approach, performing a longitudinal spatial case–control study for typhoid in Nepal, combining single-nucleotide polymorphism genotyping and case localization via global positioning. We show extensive clustering of typhoid occurring independent of population size and density. For the first time, we demonstrate an extensive range of genotypes existing within typhoid clusters, and even within individual households, including some resulting from clonal expansion. Furthermore, although the data provide evidence for direct human-to-human transmission, we demonstrate an overwhelming contribution of indirect transmission, potentially via contaminated water. Consistent with this, we detected S. Typhi and S. Paratyphi A in water supplies and found that typhoid was spatially associated with public water sources and low elevation. These findings have implications for typhoid-control strategies, and our innovative approach may be applied to other diseases caused by other monophyletic or emerging pathogens.

full-text:
Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission