A cluster of multidrug-resistant  Mycobacterium tuberculosis  among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study

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Summary

Background

The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan.

Methods

On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control.

Findings

Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation.

Interpretation

Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto.

Funding

The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG).

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Most cited references 12

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Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data

Josephine M. Bryant, Anita C. Schürch, Henk van Deutekom … (2013)

Background Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of whole genome sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the genome over relevant timescales is required. Methods We attempted to estimate a molecular clock by sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years. Results Multiple analyses support an average mutation rate of ~0.3 SNPs per genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links. Conclusions This in-depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of whole genome sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the whole genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine whole genome sequencing.

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Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis.

Courtney Maus, Bonnie Plikaytis, Thomas Shinnick (2005)

Capreomycin, an important drug for the treatment of multidrug-resistant tuberculosis, is a macrocyclic peptide antibiotic produced by Saccharothrix mutabolis subspecies capreolus. The basis of resistance to this drug was investigated by isolating and characterizing capreomycin-resistant strains of Mycobacterium smegmatis and Mycobacterium tuberculosis. Colonies resistant to capreomycin were recovered from a library of transposon-mutagenized M. smegmatis. The transposon insertion site of one mutant was mapped to an open reading frame in the unfinished M. smegmatis genome corresponding to the tlyA gene (Rv1694) in the M. tuberculosis H37Rv genome. In M. smegmatis spontaneous capreomycin-resistant mutants, the tlyA gene was disrupted by one of three different naturally occurring insertion elements. Genomic DNAs from pools of transposon mutants of M. tuberculosis H37Rv were screened by PCR by using primers to the tlyA gene and the transposon to detect mutants with an insertion in the tlyA gene. One capreomycin-resistant mutant was recovered that contained the transposon inserted at base 644 of the tlyA gene. Complementation with the wild-type tlyA gene restored susceptibility to capreomycin in the M. smegmatis and M. tuberculosis tlyA transposon mutants. Mutations were found in the tlyA genes of 28 spontaneous capreomycin-resistant mutants generated from three different M. tuberculosis strains and in the tlyA genes of capreomycin-resistant clinical isolates. In in vitro transcription-translation assays, ribosomes from tlyA mutant but not tlyA(+) strains resist capreomycin inhibition of transcription-translation. Therefore, TlyA appears to affect the ribosome, and mutation of tlyA confers capreomycin resistance.

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Directed mutagenesis of Mycobacterium smegmatis 16S rRNA to reconstruct the in vivo evolution of aminoglycoside resistance in Mycobacterium tuberculosis

Dmitri Shcherbakov, Rashid Akbergenov, Tanja Matt … (2010)

Drug resistance in Mycobacterium tuberculosis is a global problem, with major consequences for treatment and public health systems. As the emergence and spread of drug-resistant tuberculosis epidemics is largely influenced by the impact of the resistance mechanism on bacterial fitness, we wished to investigate whether compensatory evolution occurs in drug-resistant clinical isolates of M. tuberculosis. By combining information from molecular epidemiology studies of drug-resistant clinical M. tuberculosis isolates with genetic reconstructions and measurements of aminoglycoside susceptibility and fitness in Mycobacterium smegmatis, we have reconstructed a plausible pathway for how aminoglycoside resistance develops in clinical isolates of M. tuberculosis. Thus, we show by reconstruction experiments that base changes in the highly conserved A-site of 16S rRNA that: (i) cause aminoglycoside resistance, (ii) confer a high fitness cost and (iii) destabilize a stem-loop structure, are associated with a particular compensatory point mutation that restores rRNA secondary structure and bacterial fitness, while maintaining to a large extent the drug-resistant phenotype. The same types of resistance and associated mutations can be found in M. tuberculosis in clinical isolates, suggesting that compensatory evolution contributes to the spread of drug-resistant tuberculosis disease.

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Author and article information

Contributors

Peter M Keller

Journal

Journal ID (nlm-ta): Lancet Infect Dis

Journal ID (iso-abbrev): Lancet Infect Dis

Title: The Lancet. Infectious Diseases

Publisher: Elsevier Science ;, The Lancet Pub. Group

ISSN (Print): 1473-3099

ISSN (Electronic): 1474-4457

Publication date PMC-release: 1 April 2018

Publication date (Print): April 2018

Volume: 18

Issue: 4

Pages: 431-440

Affiliations

[a ]Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

[b ]Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland

[c ]Division of Communicable Diseases, Federal Office of Public Health, Bern, Switzerland

[d ]University of Zurich and Tuberculosis Center of the Swiss Lung Association, Zurich, Switzerland

[e ]European Centre for Disease Prevention and Control, Solna, Sweden

[f ]National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven, Netherlands

[g ]Center for Infectious Disease Research, Diagnostics and Perinatal Screening, Center for Infectious Disease Research, Diagnostics and Perinatal Screening, Bilthoven, Netherlands

[h ]Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany

[i ]National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany

[j ]Respiratory Infections Unit, Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany

[k ]SYNLAB Gauting and Institute of Microbiology and Laboratory Medicine, World Health Organization Supranational Reference Laboratory of Tuberculosis, Munich-Gauting, Germany

[l ]Austrian Reference Laboratory for Mycobacteria, Austrian Agency for Health and Food Safety, Vienna, Austria

[m ]Clinical Microbiology, University Hospital Basel, Basel, Switzerland

[n ]Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland

[o ]Emerging Bacterial Pathogens Unit, Division of Immunology and Infectious Diseases, San Raffaele Scientific Institute, San Raffaele Hospital, Milan, Italy

[p ]Assistance publique-Hôpitaux de Paris, Centre National de Référence de Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Bactériologie-Hygiène, Hôpitaux Universitaires Pitié Salpêtrière and Sorbonne Universités, Centre d'Imagerie Médicale Italie-Paris, CR7, Institut national de la santé et de la recherche médicale U1135, Paris, France

[q ]Irish Mycobacteria Reference Laboratory, St James's Hospital Dublin, Ireland

[r ]Department of Clinical Microbiology, Trinity College Dublin, Dublin, Ireland

[s ]Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden

[t ]National Reference Laboratory for Mycobacteria, Norwegian Institute of Public Health, Oslo, Norway

[u ]Program Tuberculosis and Mycobacteria, Operational Direction Communicable and Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Ukkel, Belgium

[v ]National Institute for Health and Welfare, Department of Infectious Diseases Surveillance and Control, Turku, Finland

[w ]Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland

[x ]Institute of Medical Microbiology, National Center for Mycobacteria, University of Zurich, Zurich, Switzerland

Author notes

[* ]Correspondence to: Dr Peter M Keller, Institute of Medical Microbiology, National Center for Mycobacteria, University of Zurich, 8006 Zurich, SwitzerlandCorrespondence to: Dr Peter M Keller, Institute of Medical MicrobiologyNational Center for MycobacteriaUniversity of ZurichZurich8006Switzerland pkeller@ 123456imm.uzh.ch

[*]

Contributed equally

[†]

Contributed equally

[‡]

Members listed at the end of the paper

Article

Publisher ID: S1473-3099(18)30004-5

DOI: 10.1016/S1473-3099(18)30004-5

PMC ID: 5864516

PubMed ID: 29326013

SO-VID: 84db7e88-28fb-43c7-9459-22acd718b4b9

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study

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Summary

Background

Methods

Findings

Interpretation

Funding

Related collections

Point-Of-Care Testing for Tuberculosis

Most cited references 12

Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data

Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis.

Directed mutagenesis of Mycobacterium smegmatis 16S rRNA to reconstruct the in vivo evolution of aminoglycoside resistance in Mycobacterium tuberculosis

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