title: Tracking a tuberculosis outbreak over 21 years: strain-specific single-nucleotide polymorphism typing combined with targeted whole-genome sequencing.
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.
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel.
authors.forename: David
authors.initials: D
authors.lastname: Stucki
authors.affiliation: Institute of Social and Preventive Medicine.
authors.forename: Marie
authors.initials: M
authors.lastname: Ballif
authors.affiliation: Institute for Infectious Diseases, University of Bern labormedizinisches zentrum Dr Risch, Liebefeld-Bern.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bodmer
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel.
authors.forename: Mireia
authors.initials: M
authors.lastname: Coscolla
authors.affiliation: Cantonal Health Authorities Bern.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Maurer
authors.affiliation: Institute for Infectious Diseases, University of Bern.
authors.forename: Sara
authors.initials: S
authors.lastname: Droz
authors.affiliation: Bernese Lung Association.
authors.forename: Christa
authors.initials: C
authors.lastname: Butz
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel.
authors.forename: Sonia
authors.initials: S
authors.lastname: Borrell
authors.affiliation: Institute for Infectious Diseases, University of Bern.
authors.forename: Christel
authors.initials: C
authors.lastname: Längle
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel.
authors.forename: Julia
authors.initials: J
authors.lastname: Feldmann
authors.affiliation: Department of Infectious Diseases, Bern University Hospital and University of Bern.
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.affiliation: Bernese Lung Association.
authors.forename: Carlo
authors.initials: C
authors.lastname: Mordasini
authors.affiliation: Federal Office of Public Health, Bern.
authors.forename: Peter
authors.initials: P
authors.lastname: Helbling
authors.affiliation: Institute of Social and Preventive Medicine, University of Zurich, Switzerland Tuberculosis Department, International Union Against Tuberculosis and Lung Disease, Paris, France.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Rieder
authors.affiliation: Institute of Social and Preventive Medicine School of Public Health and Family Medicine, University of Cape Town, South Africa.
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagneux
authors.affiliation: Swiss Tropical and Public Health Institute University of Basel Institute of Social and Preventive Medicine.
authors.forename: Lukas
authors.initials: L
authors.lastname: Fenner
mesh_terms: D000328:Adult; D000368:Aged; D015373:Bacterial Typing Techniques / Q000379:methods; D004269:DNA, Bacterial / Q000235:genetics; D004196:Disease Outbreaks; D005260:Female; D016680:Genome, Bacterial / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods; D013557:Switzerland / Q000453:epidemiology; D014376:Tuberculosis / Q000453:epidemiology* / Q000382:microbiology*
chemical_list: D004269:DNA, Bacterial
keywords: genomic epidemiology; outbreak; screening; tuberculosis; whole genome sequencing