Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris

Abstract

Candida auris was first described in 2009, and it has since caused nosocomial outbreaks, invasive infections, and fungaemia across at least 19 countries on five continents. An outbreak of C. auris occurred in a specialized cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak in the UK, involving a total of 72 patients. To understand the genetic epidemiology of C. auris infection both within this hospital and within a global context, we sequenced the outbreak isolate genomes using Oxford Nanopore Technologies and Illumina platforms to detect antifungal resistance alleles and reannotate the C. auris genome. Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin; the outbreak showed similar genetic diversity to that of the entire clade, and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1. These mutations add to a growing body of research on multiple antifungal drug targets in this organism. Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission and implement outbreak control measures.

A correction to this article is available online at https://doi.org/10.1038/s41426-018-0098-x.

A correction to this article is available online at https://doi.org/10.1038/s41426-018-0098-x.

Acknowledgements

We thank Oxford Nanopore Technologies for their generous contribution of flow cells and nanopore sequencing kits. We also wish to extend our thanks to Nicholas J. Loman (University of Birmingham) for providing insight into the initial conception of experiments and to Anastasia Litvintseva, Nancy A.M. Chow, and Kizee Etienne (Centers for Disease Control, USA) for providing additional sequence data. We also thank the sequencing team at Wellcome Trust Sanger Institute for sequencing four of the isolates presented here. J.R. was supported by an Antimicrobial Research Collaborative (ARC) early career research fellowship (RSRO_54990). R.A.F. was supported by an MIT/Wellcome Trust Fellowship. M.C.F. was supported by the Natural Environmental Research Council (NERC: NE/K014455/1) and the Medical Research Council (MRC: MR/K000373/1). D.A.-J. was supported by NERC and the Wellcome Trust. C.A.C was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Grant No. U19AI110818. D.M.A. supported by the Wellcome Trust (Grant No. 099202). Genome sequencing was provided by MicrobesNG (http://www.microbesng.uk), which is supported by the BBSRC (Grant No. BB/L024209/1).

Authors’ contributions

Clinical and outbreak data analysis: S.S. Collected isolates: S.S. Conceived experiments: J.R., M.C.F., D.A.-J., and S.S. DNA extractions: A.A., J.R. MinION DNA sequencing: J.R. Illumina sequencing: D.M.A. and MicrobesNG. Bioinformatic analysis: J.R. Genome annotation: R.A.F. and C.A.C. Manuscript preparation: J.R., R.A.F., A.A, and S.S.

Conflict of interest

J.R. received flow cells and reagents from Oxford Nanopore Technologies (ONT) free of charge, and has also presented work at a conference hosted by ONT. Authors report no other conflict of interest.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0045-x).