Nicholas R Thomson

Wellcome Trust Sanger Institute, Cambridge, England, United Kingdom

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Publications (176)1691.6 Total impact

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    ABSTRACT: Many bacterial pathogens are specialized, infecting one or few hosts, and this is often associated with more acute disease presentation. Specific genomes show markers of this specialization, which often reflect a balance between gene acquisition and functional gene loss. Within Salmonella enterica subspecies enterica, a single lineage exists that includes human and animal pathogens adapted to cause infection in different hosts, including S. enterica serovar Enteritidis (multiple hosts), S. Gallinarum (birds), and S. Dublin (cattle). This provides an excellent evolutionary context in which differences between these pathogen genomes can be related to host range. Genome sequences were obtained from ∼60 isolates selected to represent the known diversity of this lineage. Examination and comparison of the clades within the phylogeny of this lineage revealed signs of host restriction as well as evolutionary events that mark a path to host generalism. We have identified the nature and order of events for both evolutionary trajectories. The impact of functional gene loss was predicted based upon position within metabolic pathways and confirmed with phenotyping assays. The structure of S. Enteritidis is more complex than previously known, as a second clade of S. Enteritidis was revealed that is distinct from those commonly seen to cause disease in humans or animals, and that is more closely related to S. Gallinarum. Isolates from this second clade were tested in a chick model of infection and exhibited a reduced colonization phenotype, which we postulate represents an intermediate stage in pathogen-host adaptation.
    Proceedings of the National Academy of Sciences 12/2014; · 9.81 Impact Factor
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    ABSTRACT: The O antigen constitutes the outermost part of the lipopolysaccharide layer in Gram-negative bacteria. The chemical composition and structure of the O antigen show high levels of variation even within a single species revealing itself as serological diversity. Here, we present a complete sequence set for the O-antigen biosynthesis gene clusters (O-AGCs) from all 184 recognized Escherichia coli O serogroups. By comparing these sequences, we identified 161 well-defined O-AGCs. Based on the wzx/wzy or wzm/wzt gene sequences, in addition to 145 singletons, 37 serogroups were placed into 16 groups. Furthermore, phylogenetic analysis of all the E. coli O-serogroup reference strains revealed that the nearly one-quarter of the 184 serogroups were found in the ST10 lineage, which may have a unique genetic background allowing a more successful exchange of O-AGCs. Our data provide a complete view of the genetic diversity of O-AGCs in E. coli showing a stronger association between host phylogenetic lineage and O-serogroup diversification than previously recognized. These data will be a valuable basis for developing a systematic molecular O-typing scheme that will allow traditional typing approaches to be linked to genomic exploration of E. coli diversity. © The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.
    DNA research: an international journal for rapid publication of reports on genes and genomes 11/2014; · 1.73 Impact Factor
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    ABSTRACT: Enterotoxigenic Escherichia coli (ETEC), a major cause of infectious diarrhea, produce heat-stable and/or heat-labile enterotoxins and at least 25 different colonization factors that target the intestinal mucosa. The genes encoding the enterotoxins and most of the colonization factors are located on plasmids found across diverse E. coli serogroups. Whole-genome sequencing of a representative collection of ETEC isolated between 1980 and 2011 identified globally distributed lineages characterized by distinct colonization factor and enterotoxin profiles. Contrary to current notions, these relatively recently emerged lineages might harbor chromosome and plasmid combinations that optimize fitness and transmissibility. These data have implications for understanding, tracking and possibly preventing ETEC disease.
    Nature Genetics 11/2014; · 29.65 Impact Factor
  • The Lancet 11/2014; 384(9955):1720. · 39.21 Impact Factor
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    ABSTRACT: BACKGROUND: Shigellosis (previously bacillary dysentery) was the primary diarrhoeal disease of World War 1, but outbreaks still occur in military operations, and shigellosis causes hundreds of thousands of deaths per year in developing nations. We aimed to generate a high-quality reference genome of the historical Shigella flexneri isolate NCTC1 and to examine the isolate for resistance to antimicrobials. METHODS: In this genomic analysis, we sequenced the oldest extant Shigella flexneri serotype 2a isolate using single-molecule real-time (SMRT) sequencing technology. Isolated from a soldier with dysentery from the British forces fighting on the Western Front in World War 1, this bacterium, NCTC1, was the first isolate accessioned into the National Collection of Type Cultures. We created a reference sequence for NCTC1, investigated the isolate for antimicrobial resistance, and undertook comparative genetics with S flexneri reference strains isolated during the 100 years since World War 1. FINDINGS: We discovered that NCTC1 belonged to a 2a lineage of S flexneri, with which it shares common characteristics and a large core genome. NCTC1 was resistant to penicillin and erythromycin, and contained a complement of chromosomal antimicrobial resistance genes similar to that of more recent isolates. Genomic islands gained in the S flexneri 2a lineage over time were predominately associated with additional antimicrobial resistances, virulence, and serotype conversion. INTERPRETATION: This S flexneri 2a lineage is a well adapted pathogen that has continued to respond to selective pressures. We have created a valuable historical benchmark for shigellae in the form of a high-quality reference sequence for a publicly available isolate. FUNDING: The Wellcome Trust.
    The Lancet 11/2014; 384(9955):1691-7. · 39.21 Impact Factor
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    Clinical Infectious Diseases 10/2014; · 9.42 Impact Factor
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    ABSTRACT: The genus Yersinia is a large and diverse bacterial genus consisting of human pathogenic species, a fish pathogenic species, and a large number of environmental species. Recently the phylogenetic and population structure of the entire genus was elucidated through genome sequence data of 241 strains encompassing every known species in the genus. Here we report the mining of this enormous data set to create a multi-locus sequence typing-based scheme that can speciate Yersinia strains to a level of resolution equal to whole genome sequencing. Our assay is designed so that it is able to accurately sub-type the important human pathogenic species Y. enterocolitica to whole genome resolution levels. We also report the validation of the scheme on 386 strains from reference laboratory collections across Europe. We propose the scheme to be an important molecular typing system to allow accurate and reproducible speciation of Yersinia isolates, a process often inconsistent in non-specialist laboratories. Additionally our assay is the most phylogenetically informative typing scheme available for Y. enterocolitica.
    Journal of clinical microbiology. 10/2014;
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    ABSTRACT: On 28 November 2011, as part of a local food survey, Public Health England (PHE; formerly the Health Protection Agency) Food Water and Environment (FWE) Laboratory in Preston, England, confirmed the presence of Salmonella in a ready to eat watermelon slice purchased from a major supermarket retailer. The isolate was sent to the Gastrointestinal Bacteria Reference Unit (GBRU) at Colindale, London who reported it as Salmonella enterica subspecies enterica serovar Newport on 6 December 2011. On 13 December 2011, the result was communicated through the Rapid Alert System for Food and Feed (RASFF) of the European Commission [1]. In late December 2011, Health Protection Scotland (HPS) reported four cases of S. Newport, all with the same pulsed-field gel electrophoresis (PFGE) profile which had not previously been seen. Concurrently in England, Wales and Northern Ireland, reporting of S. Newport infections exceeded expected levels. Molecular analysis of isolates from the human cases from all four countries indicated a PFGE profile indistinguishable from the sliced watermelon isolate. On 13 January 2012, Germany reported through the Epidemic Intelligence Information System (EPIS) at the European Centre of Disease Prevention and Control (ECDC) fourteen S. Newport isolates that were indistinguishable from the PFGE profile of the sliced watermelon isolate. Four cases with this profile were also reported in Ireland in January 2012. A multi-agency outbreak control team (OCT) was convened on 16 January 2012 comprising staff from PHE, Public Health Wales (PHW), HPS and the United Kingdom (UK) Food Standards Agency (FSA). There were separate communications with the Robert Koch Institute (RKI) regarding the German cases and with the Health Protection Surveillance Centre (HPSC) and the National Salmonella, Shigella and Listeria Reference Laboratory (NSSLRL) regarding cases from Ireland. German and Irish public health and food safety authorities subsequently joined the OCT. The aims of investigations were to gather and collate information on exposures, to identify the potential source(s), to institute immediate control measures and to determine if there were any lessons to be learnt regarding future prevention. We describe an outbreak of S. Newport across six countries linked to the consumption of watermelon originating from Brazil.
    Euro surveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 08/2014; 19(31). · 4.66 Impact Factor
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    ABSTRACT: Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multi-drug resistance of this species. We show a remarkable intra-species genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of ca. 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents.
    Genome Biology and Evolution 07/2014; · 4.53 Impact Factor
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    ABSTRACT: Cholera infection continues to be a threat to global public health. The current cholera pandemic associated with Vibrio cholerae El Tor has now been ongoing for over half a century.
    PLoS Neglected Tropical Diseases 07/2014; 8(7):e2981. · 4.49 Impact Factor
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    ABSTRACT: Shigella flexneri is an important human pathogen that has to adapt to the anaerobic environment in the gastrointestinal tract to cause dysentery. To define the influence of anaerobiosis on the virulence of Shigella, we performed deep RNA sequencing to identify transcriptomic differences that are induced by anaerobiosis and modulated by the anaerobic Fumarate and Nitrate Reduction regulator, FNR.
    BMC Genomics 06/2014; 15(1):438. · 4.04 Impact Factor
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    ABSTRACT: The native plasmid of both Chlamydia muridarum and C. trachomatis has been shown to control virulence and infectivity in mice and in lower primates. We have recently described the development of a plasmid-based genetic transformation protocol for Chlamydia trachomatis that for the first time provides a platform for the molecular dissection of the function of the chlamydial plasmid and its individual genes or coding sequences (CDS). In the present study, we transformed a plasmid-free lymphogranuloma venereum isolate of C. trachomatis, serovar L2, with either the original shuttle vector (pGFP::SW2) or a derivative of pGFP::SW2 carrying a deletion of the plasmid CDS5 gene (pCDS5KO). Female mice were inoculated with these strains either intravaginally or transcervically. We found that transformation of the plasmid-free isolate with the intact pGFP::SW2 vector significantly enhanced infectivity and induction of host inflammatory responses when compared to the plasmid-free parental isolate. Transformation with pCDS5KO resulted in infection courses and inflammatory responses not significantly different from those observed in mice infected with the plasmid-free isolate. These results indicate a critical role of plasmid CDS5 in in vivo fitness and in induction of inflammatory responses. To our knowledge, these are the first in vivo observations ascribing infectivity and virulence to a specific plasmid gene.
    Infection and Immunity 05/2014; · 4.16 Impact Factor
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    ABSTRACT: The complete genomes of two virulent phages infecting Citrobacter rodentium are reported here for the first time. Both bacteriophages were isolated from local sewage treatment plant effluents. Genome analyses revealed a close relationship between both phages and allowed their classification as members of the Autographivirinae subfamily in the T7-like genus.
    Genome announcements. 05/2014; 2(3).
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    ABSTRACT: The genus Yersinia contains three species pathogenic for humans, one of which is the enteropathogen Yersinia pseudotuberculosis. A recent analysis by Multi Locus Sequence Typing (MLST) of the ‘Y. pseudotuberculosis complex’ revealed that this complex comprises three distinct populations: the Y. pestis/Y. pseudotuberculosis group, the recently described species Yersinia similis, and a third not yet characterized population designated ‘Korean Group’, because most strains were isolated in Korea. The aim of this study was to perform an in depth phenotypic and genetic characterization of the three populations composing the Y. pseudotuberculosis complex (excluding Y. pestis, which belonged to the Y. pseudotuberculosis cluster in the MLST analysis). Using a set of strains representative of each group, we found that the three populations had close metabolic properties, but were nonetheless distinguishable based on D-raffinose and D-melibiose fermentation, and on pyrazinamidase activity. Moreover, high-resolution electrospray mass spectrometry highlighted protein peaks characteristic of each population. Their 16S rRNA gene sequences shared high identity (≥99.5%), but specific nucleotide signatures for each group were identified. Multi-Locus Sequence Analysis also identified three genetically closely related but distinct populations. Finally, an Average Nucleotide Identity (ANI) analysis performed after sequencing the genomes of a subset of strains of each group also showed that intragroup identity (average for each group ≥99%) was higher than intergroup diversity (94.6% to 97.4%). Therefore, all phenotypic and genotypic traits studied concurred with the initial MLST data indicating that the Y. pseudotuberculosis complex comprises a third and clearly distinct population of strains forming a novel Yersinia species that we propose to designate Yersinia wautersii sp. nov. The isolation of some strains from humans, the detection of virulence genes (on the pYV and pVM82 plasmids, or encoding the superantigen ypmA) in some isolates, and the absence of pyrazinamidase activity (a hallmark of pathogenicity in the genus Yersinia) argue for the pathogenic potential of Y. wautersii.
    International journal of medical microbiology: IJMM 05/2014; · 4.54 Impact Factor
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    ABSTRACT: Lateral gene transfer (LGT) has been crucial in the evolution of the cholera pathogen, Vibrio cholerae. The two major virulence factors are present on two different mobile genetic elements, a bacteriophage containing the cholera toxin genes and a genomic island (GI) containing the intestinal adhesin genes. Non-toxigenic V. cholerae in the aquatic environment are a major source of novel DNA that allows the pathogen to morph via LGT. In this study, we report a novel GI from a non-toxigenic V. cholerae strain containing multiple genes involved in DNA repair including the recombination-repair gene recA that is 23% divergent from the indigenous recA and genes involved in the translesion synthesis pathway. This is the first report of a GI containing the critical gene recA and the first report of a GI that targets insertion into a specific site within recA. We show that possession of the island in E. coli is protective against DNA damage induced by UV-irradiation and DNA targeting antibiotics. This study highlights the importance of genetic elements such as GIs in the evolution of V. cholerae and emphasises the importance of environmental strains as a source of novel DNA that can influence the pathogenicity of toxigenic strains.
    Environmental Microbiology 05/2014; · 6.24 Impact Factor
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    ABSTRACT: The genus Yersinia has been used as a model system to study pathogen evolution. Using whole-genome sequencing of all Yersinia species, we delineate the gene complement of the whole genus and define patterns of virulence evolution. Multiple distinct ecological specializations appear to have split pathogenic strains from environmental, nonpathogenic lineages. This split demonstrates that contrary to hypotheses that all pathogenic Yersinia species share a recent common pathogenic ancestor, they have evolved independently but followed parallel evolutionary paths in acquiring the same virulence determinants as well as becoming progressively more limited metabolically. Shared virulence determinants are limited to the virulence plasmid pYV and the attachment invasion locus ail. These acquisitions, together with genomic variations in metabolic pathways, have resulted in the parallel emergence of related pathogens displaying an increasingly specialized lifestyle with a spectrum of virulence potential, an emerging theme in the evolution of other important human pathogens.
    Proceedings of the National Academy of Sciences 04/2014; 111(18):6768-73. · 9.81 Impact Factor
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    ABSTRACT: The development of genetic transformation technology for Chlamydia trachomatis using its endogenous plasmid has recently been described. C. muridarum cannot be transformed by the C. trachomatis plasmid indicating a barrier between chlamydial species. To determine which regions of the plasmid conferred the species specificity we used the novel approach of transforming wild-type C. muridarum carrying the endogenous plasmid pNigg and forced recombination with the C. trachomatis vector pGFP::SW2 which carries the complete C.trachomatis plasmid (pSW2). Penicillin and chloramphenicol resistant transformants expressing the green fluorescent protein were selected. Recovery of plasmids from these transformants showed they were recombinants. The differences between the pSW2 and pNigg allowed identification of the recombination breakpoints and showed that pGFP::SW2 had exchanged a ~1kbp region with pNigg covering CDS 2. The recombinant plasmid (pSW2NiggCDS2) is maintained under antibiotic selection when transformed into plasmid-cured C. muridarum. The ability to select for recombinants in C. muridarum shows that the barrier is not at transformation but at the level of plasmid replication or maintenance. Our studies show that CDS 2, together with adjoining sequences, is the main determinant of plasmid tropism.This article is protected by copyright. All rights reserved.
    Pathogens and Disease. 04/2014;
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    ABSTRACT: Public Health England (PHE) holds a collection of Shigella flexneri Type strains isolated between 1949 and 1972 representing 15 established serotypes and one provisional type, E1037. In this study, the genomes of all 16 PHE Type strains were sequenced using the Illumina HiSeq platform. The relationship between core genome phylogeny and serotype was examined. The most common target gene for the detection of Shigella species in clinical PCR assays, ipaH, was detected in all genomes. The type-specific target genes were correctly identified in each genome sequence. In contrast to the S. flexneri in serotype 5 strain described by Sun et al. (2012), the two PHE serotype 5 Type strains possessed an additional oac gene and were differentiated by the presence (serotype 5b) or absence (serotype 5a) of gtrX. The somatic antigen structure and phylogenetic relationship were broadly congruent for strains expressing serotype specific antigens III, IV and V, but not for those expressing I and II. The whole genome phylogenies of the 15 isolates sequenced showed that the serotype 6 Type Strain was phylogenetically distinct from the other S. flexneri serotypes sequenced. The provisional serotype E1037 fell within the serotype 4 clade, being most closely related to the Serotype 4a Type Strain. The S. flexneri genome sequences were used to evaluate phylogenetic relationships between Type strains and validate genotypic and phenotypic assays. The analysis confirmed that the PHE S. flexneri Type strains are phenotypically and genotypically distinct. Novel variants will continue to be added to this archive.
    Gut Pathogens 03/2014; 6(1):7. · 2.07 Impact Factor
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    ABSTRACT: Since 1817, seven cholera pandemics have plagued mankind. As the causative agent, Vibrio cholerae, is autochthonous in the aquatic ecosystem and some studies have revealed links between outbreaks and flux in climate and aquatic conditions, it has been widely presumed that cholera epidemics are triggered by environmental factors that promote growth of local bacterial reservoirs. However, mounting epidemiological findings and genome sequence analysis of clinical isolates indicate that epidemics are largely unassociated with most of the V. cholerae strains in aquatic ecosystems. Instead, only a specific subset of V. cholerae El Tor 'types' appears to be responsible for current epidemics. A recent report examining the evolution of a variety of V. cholerae strains indicates that the current pandemic is monophyletic and originated from a single ancestral clone that has spread globally in successive waves. In this review, we examine the clonal nature of the disease with the example of the recent history of cholera in the Americas. Epidemiological data and genome sequence-based analysis of V. cholerae isolates demonstrate that cholera epidemics of the 1990s in South America were triggered by the importation of a pathogenic V. cholerae strain that gradually spread throughout the region until local outbreaks ceased in 2001. Latin America remained virtually unaffected by the disease until a new toxigenic V. cholerae clone was imported into Haiti in 2010. Overall, cholera appears to be largely due to a subset of specific V. cholerae clones rather than the vast diversity of V. cholerae strains in the environment. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 02/2014; · 4.58 Impact Factor

Publication Stats

11k Citations
1,691.60 Total Impact Points


  • 2001–2014
    • Wellcome Trust Sanger Institute
      • Pathogen Genomics Group
      Cambridge, England, United Kingdom
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • University of Southampton
      Southampton, England, United Kingdom
  • 2012–2013
    • University of Melbourne
      • • Department of Biochemistry and Molecular Biology
      • • Department of Microbiology and Immunology
      Melbourne, Victoria, Australia
  • 2011–2012
    • Oxford University Clinical Research Unit
      Thành phố Hồ Chí Minh, Ho Chi Minh City, Vietnam
    • The University of Edinburgh
      • Royal (Dick) School of Veterinary Studies
      Edinburgh, SCT, United Kingdom
    • Erasmus MC
      • Department of Medical Microbiology and Infectious Diseases
      Rotterdam, South Holland, Netherlands
  • 2010
    • Örebro University Hospital
      • Department of Laboratory Medicine
      Örebro, Örebro, Sweden
    • Hospital for Tropical Diseases, Ho Chi Minh City
      Thành phố Hồ Chí Minh, Ho Chi Minh City, Vietnam
  • 2009
    • Biotechnology and Biological Sciences Research Council
      Swindon, England, United Kingdom
    • Universitetet i Tromsø
      Tromsø, Troms, Norway
    • Tufts University
      • Department of Developmental, Molecular and Chemical Biology
      Medford, MA, United States
  • 2003–2009
    • Imperial College London
      • • Division of Cell and Molecular Biology
      • • Centre for Molecular Microbiology and Infection
      Londinium, England, United Kingdom
  • 2008
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Birmingham
      • School of Biosciences
      Birmingham, England, United Kingdom
    • EMBL-EBI
      Cambridge, England, United Kingdom
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 1997–2008
    • University of Cambridge
      • • Department of Veterinary Medicine
      • • Department of Biochemistry
      Cambridge, England, United Kingdom
  • 2006
    • The University of York
      • Department of Biology
      York, ENG, United Kingdom