David Stucki1, Marie Ballif2, Thomas Bodmer3, Mireia Coscolla1, Anne-Marie Maurer4, Sara Droz5, Christa Butz6, Sonia Borrell1, Christel Längle5, Julia Feldmann1, Hansjakob Furrer7, Carlo Mordasini6, Peter Helbling8, Hans L Rieder9, Matthias Egger10, Sébastien Gagneux1, Lukas Fenner11. 1. Swiss Tropical and Public Health Institute University of Basel. 2. Institute of Social and Preventive Medicine. 3. Institute for Infectious Diseases, University of Bern labormedizinisches zentrum Dr Risch, Liebefeld-Bern. 4. Cantonal Health Authorities Bern. 5. Institute for Infectious Diseases, University of Bern. 6. Bernese Lung Association. 7. Department of Infectious Diseases, Bern University Hospital and University of Bern. 8. Federal Office of Public Health, Bern. 9. Institute of Social and Preventive Medicine, University of Zurich, Switzerland Tuberculosis Department, International Union Against Tuberculosis and Lung Disease, Paris, France. 10. Institute of Social and Preventive Medicine School of Public Health and Family Medicine, University of Cape Town, South Africa. 11. Swiss Tropical and Public Health Institute University of Basel Institute of Social and Preventive Medicine.
Abstract
BACKGROUND: Whole-genome sequencing (WGS) is increasingly used in molecular-epidemiological investigations of bacterial pathogens, despite cost- and time-intensive analyses. We combined strain-specific single-nucleotide polymorphism (SNP) typing and targeted WGS to investigate a tuberculosis cluster spanning 21 years in Bern, Switzerland. METHODS: On the basis of genome sequences of 3 historical outbreak Mycobacterium tuberculosis isolates, we developed a strain-specific SNP-typing assay to identify further cases. We screened 1642 patient isolates and performed WGS on all identified cluster isolates. We extracted SNPs to construct genomic networks. Clinical and social data were retrospectively collected. RESULTS: We identified 68 patients associated with the outbreak strain. Most received a tuberculosis diagnosis in 1991-1995, but cases were observed until 2011. Two thirds were homeless and/or substance abusers. Targeted WGS revealed 133 variable SNP positions among outbreak isolates. Genomic network analyses suggested a single origin of the outbreak, with subsequent division into 3 subclusters. Isolates from patients with confirmed epidemiological links differed by 0-11 SNPs. CONCLUSIONS: Strain-specific SNP genotyping allowed rapid and inexpensive identification of M. tuberculosis outbreak isolates in a population-based strain collection. Subsequent targeted WGS provided detailed insights into transmission dynamics. This combined approach could be applied to track bacterial pathogens in real time and at high resolution.
BACKGROUND: Whole-genome sequencing (WGS) is increasingly used in molecular-epidemiological investigations of bacterial pathogens, despite cost- and time-intensive analyses. We combined strain-specific single-nucleotide polymorphism (SNP) typing and targeted WGS to investigate a tuberculosis cluster spanning 21 years in Bern, Switzerland. METHODS: On the basis of genome sequences of 3 historical outbreak Mycobacterium tuberculosis isolates, we developed a strain-specific SNP-typing assay to identify further cases. We screened 1642 patient isolates and performed WGS on all identified cluster isolates. We extracted SNPs to construct genomic networks. Clinical and social data were retrospectively collected. RESULTS: We identified 68 patients associated with the outbreak strain. Most received a tuberculosis diagnosis in 1991-1995, but cases were observed until 2011. Two thirds were homeless and/or substance abusers. Targeted WGS revealed 133 variable SNP positions among outbreak isolates. Genomic network analyses suggested a single origin of the outbreak, with subsequent division into 3 subclusters. Isolates from patients with confirmed epidemiological links differed by 0-11 SNPs. CONCLUSIONS: Strain-specific SNP genotyping allowed rapid and inexpensive identification of M. tuberculosis outbreak isolates in a population-based strain collection. Subsequent targeted WGS provided detailed insights into transmission dynamics. This combined approach could be applied to track bacterial pathogens in real time and at high resolution.
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