Nicholas R Thomson

University of Nottingham, Nottigham, England, United Kingdom

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Publications (184)1736.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We analyzed 1,093 Vibrio cholerae isolates from the Democratic Republic of the Congo during 1997-2012 and found increasing antimicrobial drug resistance over time. Our study also demonstrated that the 2011-2012 epidemic was caused by an El Tor variant clonal complex with a single antimicrobial drug susceptibility profile.
    Emerging Infectious Diseases 05/2015; 21(5):847-851. DOI:10.3201/eid2105.141233 · 7.33 Impact Factor
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    ABSTRACT: Shigella is the leading cause for dysentery worldwide. Together with several virulence factors employed for invasion, the presence and length of the O antigen (OAg) of the lipopolysaccharide (LPS) plays a key role in pathogenesis. S. flexneri 2a has a bimodal OAg chain length distribution regulated in a growth-dependent manner, whereas S. sonnei LPS comprises a monomodal OAg. Here we reveal that S. sonnei, but not S. flexneri 2a, possesses a high molecular weight, immunogenic group 4 capsule, characterized by structural similarity to LPS OAg. We found that a galU mutant of S. sonnei, that is unable to produce a complete LPS with OAg attached, can still assemble OAg material on the cell surface, but a galU mutant of S. flexneri 2a cannot. High molecular weight material not linked to the LPS was purified from S. sonnei and confirmed by NMR to contain the specific sugars of the S. sonnei OAg. Deletion of genes homologous to the group 4 capsule synthesis cluster, previously described in Escherichia coli, abolished the generation of the high molecular weight OAg material. This OAg capsule strongly affects the virulence of S. sonnei. Uncapsulated knockout bacteria were highly invasive in vitro and strongly inflammatory in the rabbit intestine. But, the lack of capsule reduced the ability of S. sonnei to resist complement-mediated killing and to spread from the gut to peripheral organs. In contrast, overexpression of the capsule decreased invasiveness in vitro and inflammation in vivo compared to the wild type. In conclusion, the data indicate that in S. sonnei expression of the capsule modulates bacterial pathogenesis resulting in balanced capabilities to invade and persist in the host environment.
    PLoS Pathogens 03/2015; 11(3):e1004749. DOI:10.1371/journal.ppat.1004749 · 8.06 Impact Factor
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    ABSTRACT: Multidrug-resistant (MDR) Klebsiella pneumoniae has become a leading cause of nosocomial infections worldwide. Despite its prominence, little is known about the genetic diversity of K. pneumoniae in resource-poor hospital settings. Through whole-genome sequencing (WGS), we reconstructed an outbreak of MDR K. pneumoniae occurring on high-dependency wards in a hospital in Kathmandu during 2012 with a case-fatality rate of 75%. The WGS analysis permitted the identification of two MDR K. pneumoniae lineages causing distinct outbreaks within the complex endemic K. pneumoniae. Using phylogenetic reconstruction and lineage-specific PCR, our data predicted a scenario in which K. pneumoniae, circulating for 6 months before the outbreak, underwent a series of ward-specific clonal expansions after the acquisition of genes facilitating virulence and MDR. We suggest that the early detection of a specific NDM-1 containing lineage in 2011 would have alerted the high-dependency ward staff to intervene. We argue that some form of real-time genetic characterisation, alongside clade-specific PCR during an outbreak, should be factored into future healthcare infection control practices in both high- and low-income settings. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 02/2015; 7(3):227-239. DOI:10.15252/emmm.201404767 · 8.25 Impact Factor
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    ABSTRACT: The interaction of environmental bacteria with unicellular eukaryotes is generally considered as a major driving force for the evolution of intracellular pathogens, allowing them to survive and replicate in phagocytic cells of vertebrate hosts. To test this hypothesis on a genome wide level, we determined for the intracellular pathogen Mycobacterium marinum whether it uses conserved strategies to exploit host cells from both protozoan and vertebrate origin. Using transposon-directed insertion-site sequencing (TraDIS), we determined differences in genetic requirements for survival and replication in phagocytic cells of organisms from different kingdoms. In line with the general hypothesis, we identified a number of general virulence mechanisms, including the type VII protein secretion system ESX-1, biosynthesis of polyketide lipids and utilization of sterols. However, we could also show that M. marinum contains an even larger set of host-specific virulence determinants, including proteins involved in the modification of surface glycolipids and, surprisingly, the auxiliary proteins of the ESX-1 system. Several of these factors were in fact counterproductive in other hosts. Therefore, M. marinum contains different sets of virulence factors that are tailored for specific hosts. Our data implies that although amoeba could function as a training ground for intracellular pathogens, they do not fully prepare pathogens for crossing species barriers. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 02/2015; DOI:10.1128/IAI.03050-14 · 4.16 Impact Factor
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    ABSTRACT: Multidrug-resistant (MDR) Klebsiella pneumoniae has become a leading cause of nosocomial infections worldwide. Despite its prominence, little is known about the genetic diversity of K. pneumoniae in resource-poor hospital settings. Through whole-genome sequencing (WGS), we reconstructed an outbreak of MDR K. pneumoniae occurring on high-dependency wards in a hospital in Kathmandu during 2012 with a case-fatality rate of 75%. The WGS analysis permitted the identification of two MDR K. pneumoniae lineages causing distinct outbreaks within the complex endemic K. pneumoniae. Using phylogenetic reconstruction and lineage-specific PCR, our data predicted a scenario in which K. pneumoniae, circulating for 6 months before the outbreak, underwent a series of ward-specific clonal expansions after the acquisition of genes facilitating virulence and MDR. We suggest that the early detection of a specific NDM-1 containing lineage in 2011 would have alerted the high-dependency ward staff to intervene. We argue that some form of real-time genetic characterisation, alongside clade-specific PCR during an outbreak, should be factored into future healthcare infection control practices in both high-and low-income settings.
    EMBO Molecular Medicine 01/2015; 7:227-239. · 8.25 Impact Factor
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    ABSTRACT: The genome sequences of three strains of Salmonella enterica subsp. enterica serovar Infantis isolated from broiler chickens in 1994 and 2004 in Hungary and in the 1980s in the United Kingdom are reported here. A sequence comparison should improve our understanding of the evolution of the genome and spread of S. Infantis in poultry. Copyright © 2015 Olasz et al.
    Genome Announcements 01/2015; 3(1). DOI:10.1128/genomeA.01468-14
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    ABSTRACT: Data produced by Biolog Phenotype MicroArrays are longitudinal measurements of cells' respiration on distinct substrates. We introduce a three-step pipeline to analyze phenotypic microarray data with novel procedures for grouping, normalization and effect identification. Grouping and normalization are standard problems in the analysis of phenotype microarrays defined as categorizing bacterial responses into active and non-active, and removing systematic errors from the experimental data, respectively. We expand existing solutions by introducing an important assumption that active and non-active bacteria manifest completely different metabolism and thus should be treated separately. Effect identification, in turn, provides new insights into detecting differing respiration patterns between experimental conditions, e.g. between different combinations of strains and temperatures, as not only the main effects but also their interactions can be evaluated. In the effect identification, the multilevel data are effectively processed by a hierarchical model in the Bayesian framework. The pipeline is tested on a data set of 12 phenotypic plates with bacterium Yersinia enterocolitica. Our pipeline is implemented in R language on the top of opm R package and is freely available for research purposes.
    PLoS ONE 01/2015; 10(3):e0118392. DOI:10.1371/journal.pone.0118392 · 3.53 Impact Factor
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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; DOI:10.1073/pnas.1416707112 · 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; DOI:10.1093/dnares/dsu043 · 2.35 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; DOI:10.1038/ng.3145 · 29.65 Impact Factor
  • The Lancet 11/2014; 384(9955-9955):1720. DOI:10.1016/S0140-6736(14)61790-6 · 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(9955-9955):1691-7. DOI:10.1016/S0140-6736(14)61789-X · 39.21 Impact Factor
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    Clinical Infectious Diseases 10/2014; 60(3). DOI:10.1093/cid/ciu820 · 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.
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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.
    Eurosurveillance: 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; 6(8). DOI:10.1093/gbe/evu160 · 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. DOI:10.1371/journal.pntd.0002981 · 4.49 Impact Factor
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    ABSTRACT: Background 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. Results We found that 528 chromosomal genes were differentially expressed in response to anaerobic conditions; of these, 228 genes were also influenced by FNR. Genes that were up-regulated in anaerobic conditions are involved in carbon transport and metabolism (e.g. ptsG, manX, murQ, cysP, cra), DNA topology and regulation (e.g. ygiP, stpA, hns), host interactions (e.g. yciD, nmpC, slyB, gapA, shf, msbB) and survival within the gastrointestinal tract (e.g. shiA, ospI, adiY, cysP). Interestingly, there was a marked effect of available oxygen on genes involved in Type III secretion system (T3SS), which is required for host cell invasion and pathogenesis. These genes, located on the large Shigella virulence plasmid, were down regulated in anaerobiosis in an FNR-dependent manner. We also confirmed anaerobic induction of csrB and csrC small RNAs in an FNR-independent manner. Conclusions Anaerobiosis promotes survival and adaption strategies of Shigella, while modulating virulence plasmid genes involved in T3SS-mediated host cell invasion. The influence of FNR on this process is more extensive than previously appreciated, although aside from the virulence plasmid, this transcriptional regulator does not govern expression of genes on other horizontally acquired sequences on the chromosome such as pathogenicity islands.
    BMC Genomics 06/2014; 15(1):438. DOI:10.1186/1471-2164-15-438 · 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; 82(8). DOI:10.1128/IAI.01795-14 · 4.16 Impact Factor

Publication Stats

12k Citations
1,736.40 Total Impact Points

Institutions

  • 2015
    • University of Nottingham
      • School of Veterinary Medicine and Science
      Nottigham, England, United Kingdom
    • Nottingham Trent University
      Nottigham, England, United Kingdom
  • 2014–2015
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 2001–2015
    • Wellcome Trust Sanger Institute
      • Pathogen Genomics Group
      Cambridge, England, United Kingdom
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • University of Melbourne
      • Department of Biochemistry and Molecular Biology
      Melbourne, Victoria, Australia
  • 2012
    • Oxford University Clinical Research Unit
      Thành phố Hồ Chí Minh, Ho Chi Minh City, Vietnam
  • 2011
    • Erasmus MC
      • Department of Medical Microbiology and Infectious Diseases
      Rotterdam, South Holland, Netherlands
    • The University of Edinburgh
      • Royal (Dick) School of Veterinary Studies
      Edinburgh, SCT, United Kingdom
  • 2008–2011
    • University of Birmingham
      • • School of Immunity and Infection
      • • School of Biosciences
      Birmingham, England, United Kingdom
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 2003–2009
    • Imperial College London
      • • Division of Cell and Molecular Biology
      • • Centre for Molecular Microbiology and Infection
      Londinium, England, United Kingdom
  • 1997–2009
    • University of Cambridge
      • • Department of Biochemistry
      • • Department of Veterinary Medicine
      Cambridge, ENG, United Kingdom
  • 2002
    • The University of Warwick
      • Department of Chemistry
      Coventry, England, United Kingdom