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Research Article

Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health

Kathryn E. Holt, Heiman Wertheim, Ruth N. Zadoks, Stephen Baker, Chris A. Whitehouse, David Dance, Adam Jenney, Thomas R. Connor, Li Yang Hsu, Juliëtte Severin, Sylvain Brisse, Hanwei Cao, Jonathan Wilksch, Claire Gorrie, Mark B. Schultz, David J. Edwards, Kinh Van Nguyen, Trung Vu Nguyen, Trinh Tuyet Dao, Martijn Mensink, Vien Le Minh, Nguyen Thi Khanh Nhu, Constance Schultsz, Kuntaman Kuntaman, Paul N. Newton, Catrin E. Moore, Richard A. Strugnell, and Nicholas R. Thomson
PNAS July 7, 2015 112 (27) E3574-E3581; first published June 22, 2015; https://doi.org/10.1073/pnas.1501049112
Kathryn E. Holt
aDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
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  • For correspondence: nrt@sanger.ac.uk kholt@unimelb.edu.au
Heiman Wertheim
cOxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, National Hospital for Tropical Diseases, Hanoi, Vietnam;
dNuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom;
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Ruth N. Zadoks
eQuality Milk Production Services, Cornell University, Ithaca, NY 14853;
fInstitute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
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Stephen Baker
gThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam;
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Chris A. Whitehouse
hUnited States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
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David Dance
dNuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom;
iLao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People’s Democratic Republic;
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Adam Jenney
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
jDepartmemt Infectious Diseases and Microbiology Unit, The Alfred Hospital, Melbourne, VIC 3004, Australia;
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Thomas R. Connor
kPathogen Genomics, Wellcome Trust Sanger Centre, CB10 1SA Cambridge, United Kingdom;
lCardiff University School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, United Kingdom;
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Li Yang Hsu
mDepartment of Medicine, National University Health System, Singapore 119228;
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Juliëtte Severin
nDepartment of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands;
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Sylvain Brisse
oMicrobial Evolutionary Genomics, Institut Pasteur, CNRS, UMR3525, Paris, France;
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Hanwei Cao
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
pPeter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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Jonathan Wilksch
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
pPeter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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Claire Gorrie
aDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
pPeter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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Mark B. Schultz
aDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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David J. Edwards
aDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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Kinh Van Nguyen
qNational Hospital for Tropical Diseases, Hanoi, Vietnam;
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Trung Vu Nguyen
qNational Hospital for Tropical Diseases, Hanoi, Vietnam;
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Trinh Tuyet Dao
qNational Hospital for Tropical Diseases, Hanoi, Vietnam;
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Martijn Mensink
eQuality Milk Production Services, Cornell University, Ithaca, NY 14853;
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Vien Le Minh
gThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam;
rDivision of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA 94118-6215;
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Nguyen Thi Khanh Nhu
gThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam;
sSchool of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia;
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Constance Schultsz
gThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam;
tAcademic Medical Center, University of Amsterdam, 1012 WX Amsterdam, The Netherlands;
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Kuntaman Kuntaman
uDepartment of Clinical Microbiology, Dr. Soetomo Academic Hospital – School of Medicine, Airlangga University, Surabaya, Jawa Timur, Indonesia;
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Paul N. Newton
dNuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom;
iLao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People’s Democratic Republic;
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Catrin E. Moore
dNuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom;
iLao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People’s Democratic Republic;
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Richard A. Strugnell
bDepartment of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia;
pPeter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
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Nicholas R. Thomson
kPathogen Genomics, Wellcome Trust Sanger Centre, CB10 1SA Cambridge, United Kingdom;
vDepartment of Pathogen Molecular Biology, The London School of Hygiene and Tropical Medicine, WC1E 7HT London, United Kingdom
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  • For correspondence: nrt@sanger.ac.uk kholt@unimelb.edu.au
  1. Edited by Simon A. Levin, Princeton University, Princeton, NJ, and approved May 11, 2015 (received for review January 16, 2015)

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Significance

Klebsiella pneumoniae is rapidly becoming untreatable using last-line antibiotics. It is especially problematic in hospitals, where it causes a range of acute infections. To approach controlling such a bacterium, we first must define what it is and how it varies genetically. Here we have determined the DNA sequence of K. pneumoniae isolates from around the world and present a detailed analysis of these data. We show that there is a wide spectrum of diversity, including variation within shared sequences and gain and loss of whole genes. Using this detailed blueprint, we show that there is an unrecognized association between the possession of specific gene profiles associated with virulence and antibiotic resistance and the differing disease outcomes seen for K. pneumoniae.

Abstract

Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

  • Klebsiella pneumoniae
  • genomics
  • virulence
  • antimicrobial resistance
  • population structure

Footnotes

  • ↵1To whom correspondence may be addressed. Email: nrt{at}sanger.ac.uk or kholt{at}unimelb.edu.au.
  • Author contributions: K.E.H., H.W., R.A.S., and N.R.T. designed research; K.E.H. performed research; H.W., R.N.Z., S. Baker, C.A.W., D.D., A.J., L.Y.H., J.S., S. Brisse, H.C., J.W., K.V.N., T.V.N., T.T.D., M.M., V.L.M., N.T.K.N., C.S., K.K., P.N.N., and C.E.M. contributed new reagents/analytic tools; K.E.H., T.R.C., C.G., M.B.S., D.J.E., and N.R.T. analyzed data; and K.E.H. and N.R.T. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The sequences reported in this paper have been deposited in the European Nucleotide Archive database (accession no. ERP000165).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1501049112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Klebsiella pneumoniae, an urgent threat
Kathryn E. Holt, Heiman Wertheim, Ruth N. Zadoks, Stephen Baker, Chris A. Whitehouse, David Dance, Adam Jenney, Thomas R. Connor, Li Yang Hsu, Juliëtte Severin, Sylvain Brisse, Hanwei Cao, Jonathan Wilksch, Claire Gorrie, Mark B. Schultz, David J. Edwards, Kinh Van Nguyen, Trung Vu Nguyen, Trinh Tuyet Dao, Martijn Mensink, Vien Le Minh, Nguyen Thi Khanh Nhu, Constance Schultsz, Kuntaman Kuntaman, Paul N. Newton, Catrin E. Moore, Richard A. Strugnell, Nicholas R. Thomson
Proceedings of the National Academy of Sciences Jul 2015, 112 (27) E3574-E3581; DOI: 10.1073/pnas.1501049112

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Klebsiella pneumoniae, an urgent threat
Kathryn E. Holt, Heiman Wertheim, Ruth N. Zadoks, Stephen Baker, Chris A. Whitehouse, David Dance, Adam Jenney, Thomas R. Connor, Li Yang Hsu, Juliëtte Severin, Sylvain Brisse, Hanwei Cao, Jonathan Wilksch, Claire Gorrie, Mark B. Schultz, David J. Edwards, Kinh Van Nguyen, Trung Vu Nguyen, Trinh Tuyet Dao, Martijn Mensink, Vien Le Minh, Nguyen Thi Khanh Nhu, Constance Schultsz, Kuntaman Kuntaman, Paul N. Newton, Catrin E. Moore, Richard A. Strugnell, Nicholas R. Thomson
Proceedings of the National Academy of Sciences Jul 2015, 112 (27) E3574-E3581; DOI: 10.1073/pnas.1501049112
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