title: Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; nrt@sanger.ac.uk kholt@unimelb.edu.au.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Holt
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, National Hospital for Tropical Diseases, Hanoi, Vietnam; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom;
authors.forename: Heiman
authors.initials: H
authors.lastname: Wertheim
authors.affiliation: Quality Milk Production Services, Cornell University, Ithaca, NY 14853; Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
authors.forename: Ruth N
authors.initials: RN
authors.lastname: Zadoks
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam;
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
authors.forename: Chris A
authors.initials: CA
authors.lastname: Whitehouse
authors.affiliation: Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People's Democratic Republic;
authors.forename: David
authors.initials: D
authors.lastname: Dance
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; Departmemt Infectious Diseases and Microbiology Unit, The Alfred Hospital, Melbourne, VIC 3004, Australia;
authors.forename: Adam
authors.initials: A
authors.lastname: Jenney
authors.affiliation: Pathogen Genomics, Wellcome Trust Sanger Centre, CB10 1SA Cambridge, United Kingdom; Cardiff University School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, United Kingdom;
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Connor
authors.affiliation: Department of Medicine, National University Health System, Singapore 119228;
authors.forename: Li Yang
authors.initials: LY
authors.lastname: Hsu
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands;
authors.forename: Juliëtte
authors.initials: J
authors.lastname: Severin
authors.affiliation: Microbial Evolutionary Genomics, Institut Pasteur, CNRS, UMR3525, Paris, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brisse
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; Peter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Hanwei
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; Peter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilksch
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; Peter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Claire
authors.initials: C
authors.lastname: Gorrie
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Mark B
authors.initials: MB
authors.lastname: Schultz
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: David J
authors.initials: DJ
authors.lastname: Edwards
authors.affiliation: National Hospital for Tropical Diseases, Hanoi, Vietnam;
authors.forename: Kinh Van
authors.initials: KV
authors.lastname: Nguyen
authors.affiliation: National Hospital for Tropical Diseases, Hanoi, Vietnam;
authors.forename: Trung Vu
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: National Hospital for Tropical Diseases, Hanoi, Vietnam;
authors.forename: Trinh Tuyet
authors.initials: TT
authors.lastname: Dao
authors.affiliation: Quality Milk Production Services, Cornell University, Ithaca, NY 14853;
authors.forename: Martijn
authors.initials: M
authors.lastname: Mensink
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA 94118-6215;
authors.forename: Vien Le
authors.initials: VL
authors.lastname: Minh
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: Nguyen Thi Khanh
authors.initials: NT
authors.lastname: Nhu
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Academic Medical Center, University of Amsterdam, 1012 WX Amsterdam, The Netherlands;
authors.forename: Constance
authors.initials: C
authors.lastname: Schultsz
authors.affiliation: Department of Clinical Microbiology, Dr. Soetomo Academic Hospital - School of Medicine, Airlangga University, Surabaya, Jawa Timur, Indonesia;
authors.forename: Kuntaman
authors.initials: K
authors.lastname: Kuntaman
authors.affiliation: Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People's Democratic Republic;
authors.forename: Paul N
authors.initials: PN
authors.lastname: Newton
authors.affiliation: Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, OX3 7BN Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People's Democratic Republic;
authors.forename: Catrin E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia; Peter Doherty Institute, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Strugnell
authors.affiliation: Pathogen Genomics, Wellcome Trust Sanger Centre, CB10 1SA Cambridge, United Kingdom; Department of Pathogen Molecular Biology, The London School of Hygiene and Tropical Medicine, WC1E 7HT London, United Kingdom nrt@sanger.ac.uk kholt@unimelb.edu.au.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000145:classification / Q000235:genetics; D003428:Cross Infection / Q000382:microbiology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D005798:Genes, Bacterial / Q000235:genetics; D014644:Genetic Variation; D016680:Genome, Bacterial / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D010802:Phylogeny; D011157:Population Dynamics; D011634:Public Health / Q000706:statistics & numerical data / Q000639:trends; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D014774:Virulence / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins
keywords: Klebsiella pneumoniae; antimicrobial resistance; genomics; population structure; virulence