Imperial College London

DrXavierDidelot

Faculty of MedicineSchool of Public Health

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3622x.didelot

 
 
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Location

 

G30Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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168 results found

Larsen J, Raisen CL, Ba X, Sadgrove NJ, Padilla-González GF, Simmonds MSJ, Loncaric I, Kerschner H, Apfalter P, Hartl R, Deplano A, Vandendriessche S, Černá Bolfíková B, Hulva P, Arendrup MC, Hare RK, Barnadas C, Stegger M, Sieber RN, Skov RL, Petersen A, Angen Ø, Rasmussen SL, Espinosa-Gongora C, Aarestrup FM, Lindholm LJ, Nykäsenoja SM, Laurent F, Becker K, Walther B, Kehrenberg C, Cuny C, Layer F, Werner G, Witte W, Stamm I, Moroni P, Jørgensen HJ, de Lencastre H, Cercenado E, García-Garrote F, Börjesson S, Hæggman S, Perreten V, Teale CJ, Waller AS, Pichon B, Curran MD, Ellington MJ, Welch JJ, Peacock SJ, Seilly DJ, Morgan FJE, Parkhill J, Hadjirin NF, Lindsay JA, Holden MTG, Edwards GF, Foster G, Paterson GK, Didelot X, Holmes MA, Harrison EM, Larsen ARet al., 2022, Emergence of methicillin resistance predates the clinical use of antibiotics., Nature

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

Journal article

Ortiz AT, Coronel J, Vidal JR, Bonilla C, Moore DAJ, Gilman RH, Balloux F, Kon OM, Didelot X, Grandjean Let al., 2021, Genomic signatures of pre-resistance in Mycobacterium tuberculosis, NATURE COMMUNICATIONS, Vol: 12

Journal article

Helekal D, Ledda A, Volz E, Wyllie D, Didelot Xet al., 2021, Bayesian inference of clonal expansions in a dated phylogeny., Syst Biol

Microbial population genetics models often assume that all lineages are constrained by the same population size dynamics over time. However, many neutral and selective events can invalidate this assumption, and can contribute to the clonal expansion of a specific lineage relative to the rest of the population. Such differential phylodynamic properties between lineages result in asymmetries and imbalances in phylogenetic trees that are sometimes described informally but which are difficult to analyse formally. To this end, we developed a model of how clonal expansions occur and affect the branching patterns of a phylogeny. We show how the parameters of this model can be inferred from a given dated phylogeny using Bayesian statistics, which allows us to assess the probability that one or more clonal expansion events occurred. For each putative clonal expansion event we estimate its date of emergence and subsequent phylodynamic trajectory, including its long-term evolutionary potential which is important to determine how much effort should be placed on specific control measures. We demonstrate the applicability of our methodology on simulated and real datasets. Inference under our clonal expansion model can reveal important features in the evolution and epidemiology of infectious disease pathogens.

Journal article

Didelot X, Parkhill J, 2021, A scalable analytical approach from bacterial genomes to epidemiology

<jats:title>Summary</jats:title><jats:p>Recent years have seen a remarkable increase in the practicality of sequencing whole genomes from large numbers of bacterial isolates. The availability of this data has huge potential to deliver new insights into the evolution and epidemiology of bacterial pathogens, but the scalability of the analytical methodology has been lagging behind that of the sequencing technology. Here we present a step-by-step approach for such large-scale genomic epidemiology analyses, from bacterial genomes to epidemiological interpretations. A central component of this approach is the dated phylogeny, which is a phylogenetic tree with branch lengths measured in units of time. The construction of dated phylogenies from bacterial genomic data needs to account for the disruptive effect of recombination on phylogenetic relationships, and we describe how this can be achieved. Dated phylogenies can then be used to perform fine-scale or large-scale epidemiological analyses, depending on the proportion of cases for which genomes are available. A key feature of this approach is computational scalability, and in particular the ability to process hundreds or thousands of genomes within a matter of hours. This is a clear advantage of the step-by-step approach described here. We discuss other advantages and disadvantages of the approach, as well as potential improvements and avenues for future research.</jats:p>

Journal article

Boonyasiri A, Myall AC, Wan Y, Bolt F, Ledda A, Mookerjee S, Weiße AY, Turton JF, Abbas H, Prakapaite R, Sabnis A, Abdolrasouli A, Malpartida-Cardenas K, Miglietta L, Donaldson H, Gilchrist M, Hopkins KL, Ellington MJ, Otter JA, Larrouy-Maumus G, Edwards AM, Rodriguez-Manzano J, Didelot X, Barahona M, Holmes AH, Jauneikaite E, Davies Fet al., 2021, Integrated patient network and genomic plasmid analysis reveal a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes

<jats:title>Abstract</jats:title><jats:p>The incidence of carbapenemase-producing Enterobacterales (CPE) is rising globally, yet Imipenemase (IMP) carbapenemases remain relatively rare. This study describes an investigation of the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network.</jats:p><jats:p>A network analysis approach to patient pathways, using routinely collected electronic health records, identified previously unrecognised contacts between patients who were IMP CPE positive on screening, implying potential bacterial transmission events. Whole genome sequencing of 85 Enterobacterales isolates from these patients revealed that 86% (73/85) were diverse species (predominantly <jats:italic>Klebsiella</jats:italic> spp, <jats:italic>Enterobacter</jats:italic> spp, <jats:italic>E. coli</jats:italic>) and harboured an IncHI2 plasmid, which carried both <jats:italic>bla</jats:italic><jats:sub>IMP</jats:sub> and the putative mobile colistin resistance gene <jats:italic>mcr-9</jats:italic>. Detailed phylogenetic analysis identified two distinct IncHI2 plasmid lineages, A and B, both of which showed significant association with patient movements between four hospital sites and across medical specialities.</jats:p><jats:p>Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of <jats:italic>bla</jats:italic><jats:sub>IMP</jats:sub>CPE, which remained unidentified during standard microbiology and infection control investigations. With whole genome sequencing (WGS) technologies and large-data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Analysing outbreaks at the plasmid level reveal

Journal article

Wang L, Didelot X, Bi Y, Gao GFet al., 2021, Assessing the extent of community spread caused by mink-derived SARS-CoV-2 variants., Innovation (N Y), Vol: 2

SARS-CoV-2 has recently been found to have spread from humans to minks and then to have transmitted back to humans. However, it is unknown to what extent the human-to-human transmission caused by the variant has reached. Here, we used publicly available SARS-CoV-2 genomic sequences from both humans and minks collected in Denmark and the Netherlands, and combined phylogenetic analysis with Bayesian inference under an epidemiological model, to trace the possibility of person-to-person transmission. The results showed that at least 12.5% of all people being infected with dominated mink-derived SARS-CoV-2 variants in Denmark and the Netherlands were caused by human-to-human transmission, indicating that this "back-to-human" SARS-CoV-2 variant has already caused human-to-human transmission. Our study also indicated the need for monitoring this mink-derived and other animal source "back-to-human" SARS-CoV-2 in future and that prevention and control measures should be tailored to avoid large-scale community transmission caused by the virus jumping between animals and humans.

Journal article

Didelot X, Geidelberg L, COVID-19 Genomics UK COG-UK consortium, Volz EMet al., 2021, Model design for non-parametric phylodynamic inference and applications to pathogen surveillance., bioRxiv

Inference of effective population size from genomic data can provide unique information about demographic history, and when applied to pathogen genetic data can also provide insights into epidemiological dynamics. The combination of non-parametric models for population dynamics with molecular clock models which relate genetic data to time has enabled phylodynamic inference based on large sets of time-stamped genetic sequence data. The methodology for non-parametric inference of effective population size is well-developed in the Bayesian setting, but here we develop a frequentist approach based on non-parametric latent process models of population size dynamics. We appeal to statistical principles based on out-of-sample prediction accuracy in order to optimize parameters that control shape and smoothness of the population size over time. We demonstrate the flexibility and speed of this approach in a series of simulation experiments, and apply the methodology to reconstruct the previously described waves in the seventh pandemic of cholera. We also estimate the impact of non-pharmaceutical interventions for COVID-19 in England using thousands of SARS-CoV-2 sequences. By incorporating a measure of the strength of these interventions over time within the phylodynamic model, we estimate the impact of the first national lockdown in the UK on the epidemic reproduction number.

Journal article

Helekal D, Ledda A, Volz E, Wyllie D, Didelot Xet al., 2021, Bayesian inference of clonal expansions in a dated phylogeny

<jats:title>ABSTRACT</jats:title><jats:p>Microbial population genetics models often assume that all lineages are constrained by the same population size dynamics over time. However, many neutral and selective events can invalidate this assumption, and can contribute to the clonal expansion of a specific lineage relative to the rest of the population. Such differential phylodynamic properties between lineages result in asymmetries and imbalances in phylogenetic trees that are sometimes described informally but which are difficult to analyse formally. To this end, we developed a model of how clonal expansions occur and affect the branching patterns of a phylogeny. We show how the parameters of this model can be inferred from a given dated phylogeny using Bayesian statistics, which allows us to assess the probability that one or more clonal expansion events occurred. For each putative clonal expansion event we estimate their date of emergence and subsequent phylodynamic trajectories, including their long-term evolutionary potential which is important to determine how much effort should be placed on specific control measures. We demonstrate the applicability of our methodology on simulated and real datasets.</jats:p>

Journal article

Knight DR, Imwattana K, Kullin B, Guerrero-Araya E, Paredes-Sabja D, Didelot X, Dingle KE, Eyre DW, Rodriguez C, Riley Tet al., 2021, Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy, ELIFE, Vol: 10, ISSN: 2050-084X

Journal article

Nimmo C, van Dorp L, Ortiz AT, Pang J, Acman M, Millard J, Padayatchi N, Grant A, O'Donnell M, Brynildsrud O, Eldholm V, Grandjean L, Didelot X, Balloux Fet al., 2021, BEDAQUILINE RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS PREDATES ITS CLINICAL USE, Publisher: BMJ PUBLISHING GROUP, Pages: A51-A52, ISSN: 0040-6376

Conference paper

Didelot X, Kendall M, Xu Y, White PJ, McCarthy Net al., 2021, Genomic epidemiology analysis of infectious disease outbreaks using TransPhylo., Current Protocols, Vol: 1, Pages: 1-23, ISSN: 2691-1299

Comparing the pathogen genomes from several cases of an infectious disease has the potential to help us understand and control outbreaks. Many methods exist to reconstruct a phylogeny from such genomes, which represents how the genomes are related to one another. However, such a phylogeny is not directly informative about transmission events between individuals. TransPhylo is a software tool implemented as an R package designed to bridge the gap between pathogen phylogenies and transmission trees. TransPhylo is based on a combined model of transmission between hosts and pathogen evolution within each host. It can simulate both phylogenies and transmission trees jointly under this combined model. TransPhylo can also reconstruct a transmission tree based on a dated phylogeny, by exploring the space of transmission trees compatible with the phylogeny. A transmission tree can be represented as a coloring of a phylogeny where each color represents a different host of the pathogen, and TransPhylo provides convenient ways to plot these colorings and explore the results. This article presents the basic protocols that can be used to make the most of TransPhylo. © 2021 The Authors. Basic Protocol 1: First steps with TransPhylo Basic Protocol 2: Simulation of outbreak data Basic Protocol 3: Inference of transmission Basic Protocol 4: Exploring the results of inference.

Journal article

Lassalle F, Dastgheib SMM, Zhao F-J, Zhang J, Verbag S, Fruhling A, Brinkmann H, Osborne T, Sikorski J, Balloux F, Didelot X, Santini J, Petersen Jet al., 2021, Phylogenomics reveals the basis of adaptation of Pseudorhizobium species to extreme environments and supports a taxonomic revision of the genus, Systematic and Applied Microbiology, Vol: 44, Pages: 1-14, ISSN: 0172-5564

The family Rhizobiaceae includes many genera of soil bacteria, often isolated for their association with plants. Herein, we investigate the genomic diversity of a group of Rhizobium species and unclassified strains isolated from atypical environments, including seawater, rock matrix or polluted soil. Based on whole-genome similarity and core genome phylogeny, we show that this group corresponds to the genus Pseudorhizobium. We thus reclassify Rhizobium halotolerans, R. marinum, R. flavum and R. endolithicum as P. halotolerans sp. nov., P. marinum comb. nov. , P. flavum comb. nov. and P. endolithicum comb. nov. , respectively, and show that P. pelagicum is a synonym of P. marinum . We also delineate a new chemolithoautotroph species, P. banfieldiae sp. nov. , whose type strain is NT-26 T (= DSM 106348 T = CFBP 8663 T ) . This genome-based classification was supported by a chemotaxonomic comparison, with increasing taxonomic resolution provided by fatty acid, protein and metabolic profiles. In addition, we used a phylogenetic approach to infer scenarios of duplication, horizontal transfer and loss for all genes in the Pseudorhizobium pangenome. We thus identify the key functions associated with the diversification of each species and higher clades, shedding light on the mechanisms of adaptation to their respective ecological niches. Respiratory proteins acquired at the origin of Pseudorhizobium were combined with clade-specific genes to enable different strategies for detoxification and nutrition in harsh, nutrient- poor environments.

Journal article

Didelot X, Siveroni I, Volz EM, 2021, Additive uncorrelated relaxed clock models for the dating of genomic epidemiology phylogenies, Molecular Biology and Evolution, Vol: 38, Pages: 307-317, ISSN: 0737-4038

Phylogenetic dating is one of the most powerful and commonly used methods of drawing epidemiological interpretations from pathogen genomic data. Building such trees requires considering a molecular clock model which represents the rate at which substitutions accumulate on genomes. When the molecular clock rate is constant throughout the tree then the clock is said to be strict, but this is often not an acceptable assumption. Alternatively, relaxed clock models consider variations in the clock rate, often based on a distribution of rates for each branch. However, we show here that the distributions of rates across branches in commonly used relaxed clock models are incompatible with the biological expectation that the sum of the numbers of substitutions on two neighbouring branches should be distributed as the substitution number on a single branch of equivalent length. We call this expectation the additivity property. We further show how assumptions of commonly used relaxed clock models can lead to estimates of evolutionary rates and dates with low precision and biased confidence intervals. We therefore propose a new additive relaxed clock model where the additivity property is satisfied. We illustrate the use of our new additive relaxed clock model on a range of simulated and real datasets, and we show that using this new model leads to more accurate estimates of mean evolutionary rates and ancestral dates.

Journal article

Didelot X, 2021, Phylogenetic Methods for Genome-Wide Association Studies in Bacteria., Methods Mol Biol, Vol: 2242, Pages: 205-220

Genome-wide association studies in bacteria have great potential to deliver a better understanding of the genetic basis of many biologically important phenotypes, including antibiotic resistance, pathogenicity, and host adaptation. Such studies need however to account for the specificities of bacterial genomics, especially in terms of population structure, homologous recombination, and genomic plasticity. A powerful way to tackle this challenge is to use a phylogenetic approach, which is based on long-standing methodology for the evolutionary analysis of bacterial genomic data. Here we present both the theoretical and practical aspects involved in the use of phylogenetic methods for bacterial genome-wide association studies.

Journal article

Hennart M, Panunzi LG, Rodrigues C, Gaday Q, Baines SL, Barros-Pinkelnig M, Carmi-Leroy A, Dazas M, Wehenkel AM, Didelot X, Toubiana J, Badell E, Brisse Set al., 2020, Population genomics and antimicrobial resistance in Corynebacterium diphtheriae, GENOME MEDICINE, Vol: 12, ISSN: 1756-994X

Journal article

Fountain-Jones NM, Appaw RC, Carver S, Didelot X, Volz E, Charleston Met al., 2020, Emerging phylogenetic structure of the SARS-CoV-2 pandemic., Virus Evol, Vol: 6, ISSN: 2057-1577

Since spilling over into humans, SARS-CoV-2 has rapidly spread across the globe, accumulating significant genetic diversity. The structure of this genetic diversity and whether it reveals epidemiological insights are fundamental questions for understanding the evolutionary trajectory of this virus. Here, we use a recently developed phylodynamic approach to uncover phylogenetic structures underlying the SARS-CoV-2 pandemic. We find support for three SARS-CoV-2 lineages co-circulating, each with significantly different demographic dynamics concordant with known epidemiological factors. For example, Lineage C emerged in Europe with a high growth rate in late February, just prior to the exponential increase in cases in several European countries. Non-synonymous mutations that characterize Lineage C occur in functionally important gene regions responsible for viral replication and cell entry. Even though Lineages A and B had distinct demographic patterns, they were much more difficult to distinguish. Continuous application of phylogenetic approaches to track the evolutionary epidemiology of SARS-CoV-2 lineages will be increasingly important to validate the efficacy of control efforts and monitor significant evolutionary events in the future.

Journal article

Zhao L, Chen H, Didelot X, Li Z, Li Y, Chen M, Du Y, Zhao H, Li J, Hu Q, Kan B, Chen M, Pang Bet al., 2020, Co-existence of multiple distinct lineages in Vibrio parahaemolyticus serotype O4:K12, MICROBIAL GENOMICS, Vol: 6, ISSN: 2057-5858

Journal article

Osnes MN, Didelot X, de Korne-Elenbaas J, Alfsnes K, Brynildsrud OB, Syversen G, Nilsen OJ, De Blasio BF, Caugant DA, Eldholm Vet al., 2020, Sudden emergence of a Neisseria gonorrhoeae Glade with reduced susceptibility to extended-spectrum cephalosporins, Norway, MICROBIAL GENOMICS, Vol: 6, ISSN: 2057-5858

Journal article

Celma CC, Beard S, Douglas A, Wong S, Osafo N-K, Hannah M, Hale A, Huggins G, Ladhani S, Dunning J, Vegvari C, Grad Y, White P, Didelot X, Whittles L, Scangarella-Oman N, Mitrani-Gold F, Dumont E, Perry C, Gilchrist K, Hossain M, Mortimer T, Anderson R, Gardiner Det al., 2020, Retrospective analysis on confirmation rates for referred positive rotavirus samples in England, 2016 to 2017: implications for diagnosis and surveillance, Eurosurveillance, Vol: 25, Pages: 1-8, ISSN: 1025-496X

BackgroundRapid diagnostic tests are commonly used by hospital laboratories in England to detect rotavirus (RV), and results are used to inform clinical management and support national surveillance of the infant rotavirus immunisation programme since 2013. In 2017, the Public Health England (PHE) national reference laboratory for enteric viruses observed that the presence of RV could not be confirmed by PCR in a proportion of RV-positive samples referred for confirmatory detection.AimWe aimed to compare the positivity rate of detection methods used by hospital laboratories with the PHE confirmatory test rate.MethodsRotavirus specimens testing positive at local hospital laboratories were re-tested at the PHE national reference laboratory using a PCR test. Confirmatory results were compared to original results from the PHE laboratory information management system.ResultsHospital laboratories screened 70.1% (2,608/3,721) of RV samples using immunochromatographic assay (IC) or rapid tests, 15.5% (578/3,721) using enzyme immunoassays (EIA) and 14.4% (535/3,721) using PCR. Overall, 1,011/3,721 (27.2%) locally RV-positive samples referred to PHE in 2016 and 2017 failed RV detection using the PHE reference laboratory PCR test. Confirmation rates were 66.9% (1,746/2,608) for the IC tests, 87.4% (505/578) for the EIA and 86.4% (465/535) for the PCR assays. Seasonal confirmation rate discrepancies were also evident for IC tests.ConclusionsThis report highlights high false positive rates with the most commonly used RV screening tests and emphasises the importance of implementing verified confirmatory tests for RV detections. This has implications for clinical diagnosis and national surveillance.

Journal article

Whittles LK, White PJ, Didelot X, 2020, Assessment of the potential of vaccination to combat antibiotic resistance in gonorrhea: a modeling analysis to determine preferred product characteristics, Clinical Infectious Diseases, Vol: 71, Pages: 1912-1919, ISSN: 1058-4838

BACKGROUND: Gonorrhea incidence is increasing rapidly in many countries, whilst antibiotic resistance is making treatment more difficult. Combined with evidence that MeNZB and Bexsero meningococcal vaccines are likely partially-protective against gonorrhea, this has renewed interest in a gonococcal vaccine, and several candidates are in development. Key questions are how protective a vaccine needs to be, how long protection needs to last, and how should it be targeted. We assessed vaccination's potential impact, and the feasibility of achieving WHO's target 90% reduction in gonorrhea incidence 2016-2030, by comparing realistic vaccination strategies under a range of scenarios of vaccine efficacy and duration of protection, and emergence of extensively-resistant gonorrhea. METHODS: We developed a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behavior in men-who-have-sex-with-men (MSM). We used data from England, which has a comprehensive, consistent nationwide surveillance system. Using particle Markov Chain Monte Carlo methods we fitted the model to gonorrhea incidence in 2008-17, and then used Bayesian forecasting to examine an extensive range of scenarios. RESULTS: Even in the worst-case scenario of untreatable infection emerging, the WHO target is achievable if all MSM attending sexual health clinics receive a vaccine offering ≥52% protection for ≥6 years. A vaccine conferring 31% protection (as estimated for MeNZB) for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of resistant gonorrhea remains treatable. CONCLUSIONS: Even a partially-protective vaccine, delivered through a realistic targeting strategy, could substantially reduce gonorrhea incidence, despite antibiotic resistance.

Journal article

Wang L, Didelot X, Yang J, Wong G, Shi Y, Liu W, Gao GF, Bi Yet al., 2020, Inference of person-to-person transmission of COVID-19 reveals hidden super-spreading events during the early outbreak phase, NATURE COMMUNICATIONS, Vol: 11

Journal article

Janezic S, Dingle K, Alvin J, Accetto T, Didelot X, Crook DW, Lacy DB, Rupnik Met al., 2020, Comparative genomics of Clostridioides difficile toxinotypes identifies module-based toxin gene evolution, MICROBIAL GENOMICS, Vol: 6, ISSN: 2057-5858

Journal article

Knight DR, Imwattana K, Kullin B, Guerrero-Araya E, Paredes-Sabja D, Didelot X, Dingle KE, Eyre DW, Rodríguez C, Riley TVet al., 2020, The Clostridioides difficile species problem: global phylogenomic analysis uncovers three ancient, toxigenic, genomospecies

<jats:title>Abstract</jats:title><jats:p><jats:italic>Clostridioides difficile</jats:italic> infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across <jats:italic>C. difficile</jats:italic> underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 <jats:italic>C. difficile</jats:italic> genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of <jats:italic>C. difficile</jats:italic> specifically and taxonomy of the <jats:italic>Peptostreptococcaceae</jats:italic> in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of <jats:italic>C. difficile</jats:italic> and close relatives. Beyond the taxonomic ramifications, this work impacts the diagnosis of CDI worldwide.</jats:p>

Journal article

Volz E, Wiuf C, Grad YH, Frost SDW, Dennis AM, Didelot Xet al., 2020, Identification of hidden population structure in time-scaled phylogenies, Systematic Biology, Vol: 69, Pages: 884-896, ISSN: 1063-5157

Abstract Population structure influences genealogical patterns, however data pertaining to how populations are structured are often unavailable or not directly observable. Inference of population structure is highly important in molecular epidemiology where pathogen phylogenetics is increasingly used to infer transmission patterns and detect outbreaks. Discrepancies between observed and idealised genealogies, such as those generated by the coalescent process, can be quantified, and where significant differences occur, may reveal the action of natural selection, host population structure, or other demographic and epidemiological heterogeneities. We have developed a fast non-parametric statistical test for detection of cryptic population structure in time-scaled phylogenetic trees. The test is based on contrasting estimated phylogenies with the theoretically expected phylodynamic ordering of common ancestors in two clades within a coalescent framework. These statistical tests have also motivated the development of algorithms which can be used to quickly screen a phylogenetic tree for clades which are likely to share a distinct demographic or epidemiological history. Epidemiological applications include identification of outbreaks in vulnerable host populations or rapid expansion of genotypes with a fitness advantage. To demonstrate the utility of these methods for outbreak detection, we applied the new methods to large phylogenies reconstructed from thousands of HIV-1 partial pol sequences. This revealed the presence of clades which had grown rapidly in the recent past, and was significantly concentrated in young men, suggesting recent and rapid transmission in that group. Furthermore, to demonstrate the utility of these methods for the study of antimicrobial resistance, we applied the new methods to a large phylogeny reconstructed from whole genome Neisseria gonorrhoeae sequences. We find that population structure detected using these methods closely overlaps with th

Journal article

Lassalle F, Didelot X, 2020, Bacterial microevolution and the pangenome, The Pangenome: Diversity, Dynamics and Evolution of Genomes, Pages: 129-149, ISBN: 9783030382803

The comparison of multiple genome sequences sampled from a bacterial population reveals considerable diversity in both the core and the accessory parts of the pangenome. This diversity can be analysed in terms of microevolutionary events that took place since the genomes shared a common ancestor, especially deletion, duplication, and recombination. We review the basic modelling ingredients used implicitly or explicitly when performing such a pangenome analysis. In particular, we describe a basic neutral phylogenetic framework of bacterial pangenome microevolution, which is not incompatible with evaluating the role of natural selection. We survey the different ways in which pangenome data is summarised in order to be included in microevolutionary models, as well as the main methodological approaches that have been proposed to reconstruct pangenome microevolutionary history.

Book chapter

Ledda A, Cummins M, Shaw LP, Jauneikaite E, Cole K, Lasalle F, Barry D, Rosmarin C, Anaraki S, Wareham D, Stoesser N, Paul J, Manuel R, Cherian BP, Didelot Xet al., 2020, Hospital outbreak of carbapenem-resistant Enterobacteriales associated with an OXA-48 plasmid carried mostly byEscherichia coliST399

<jats:title>Abstract</jats:title><jats:p>A hospital outbreak of carbapenem-resistant Enterobacteriales was detected by routine surveillance. Whole genome sequencing and subsequent analysis revealed a conserved promiscuous OXA-48 carrying plasmid as the defining factor within this outbreak. Four different species of Enterobacteriales were involved in the outbreak.<jats:italic>Escherichia coli</jats:italic>ST399 accounted for 20/55 of all the isolates. Comparative genomics with publicly available<jats:italic>E. coli</jats:italic>ST399 sequence data showed that the outbreak isolates formed a unique clade. The OXA-48 plasmid identified in the outbreak differed from other known plasmids by an estimated five homologous recombination events. We estimated a lower bound to the plasmid conjugation rate to be 0.23 conjugation events per lineage per year. Our analysis suggests co-evolution between the plasmid and its main bacterial host to be a key driver of the outbreak. This is the first study to report carbapenem-resistant<jats:italic>E. coli</jats:italic>ST399 carrying OXA48 as the main cause of a plasmid-borne outbreak within a hospital setting. This study supports complementary roles for both plasmid conjugation and clonal expansion in the emergence of this outbreak.</jats:p>

Journal article

Rodriguez Manzano J, Moser N, Malpartida Cardenas K, Moniri A, Fisarova L, Pennisi I, Boonyasiri A, Jauneikaite E, Abdolrasouli A, Otter J, Bolt F, Davies F, Didelot X, Holmes A, Georgiou Pet al., 2020, Rapid detection of mobilized colistin resistance using a nucleic acid based lab-on-a-chip diagnostic system, Scientific Reports, Vol: 10, ISSN: 2045-2322

The increasing prevalence of antimicrobial resistance is a serious threat to global public health. One of the most concerning trends is the rapid spread of Carbapenemase-Producing Organisms (CPO), where colistin has become the last-resort antibiotic treatment. The emergence of colistin resistance, including the spread of mobilized colistin resistance (mcr) genes, raises the possibility of untreatable bacterial infections and motivates the development of improved diagnostics for the detection of colistin-resistant organisms. This work demonstrates a rapid response for detecting the most recently reported mcr gene, mcr−9, using a portable and affordable lab-on-a-chip (LoC) platform, offering a promising alternative to conventional laboratory-based instruments such as real-time PCR (qPCR). The platform combines semiconductor technology, for non-optical real-time DNA sensing, with a smartphone application for data acquisition, visualization and cloud connectivity. This technology is enabled by using loop-mediated isothermal amplification (LAMP) as the chemistry for targeted DNA detection, by virtue of its high sensitivity, specificity, yield, and manageable temperature requirements. Here, we have developed the first LAMP assay for mcr−9 - showing high sensitivity (down to 100 genomic copies/reaction) and high specificity (no cross-reactivity with other mcr variants). This assay is demonstrated through supporting a hospital investigation where we analyzed nucleic acids extracted from 128 carbapenemase-producing bacteria isolated from clinical and screening samples and found that 41 carried mcr−9 (validated using whole genome sequencing). Average positive detection times were 6.58 ± 0.42 min when performing the experiments on a conventional qPCR instrument (n = 41). For validating the translation of the LAMP assay onto a LoC platform, a subset of the samples were tested (n = 20), showing average detection times o

Journal article

Hennart M, Panunzi LG, Rodrigues C, Gaday Q, Baines SL, Barros-Pinkelnig M, Carmi-Leroy A, Dazas M, Wehenkel A-M, Didelot X, Toubiana J, Badell E, Brisse Set al., 2020, Population genomics and antimicrobial resistance inCorynebacterium diphtheriae

<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Corynebacterium diphtheriae</jats:italic>, the agent of diphtheria, is a genetically diverse bacterial species. Although antimicrobial resistance has emerged against several drugs including first-line penicillin, the genomic determinants and population dynamics of resistance are largely unknown for this neglected human pathogen.</jats:p><jats:p>Here we analyzed the associations of antimicrobial susceptibility phenotypes, diphtheria toxin production and genomic features in<jats:italic>C. diphtheriae.</jats:italic>We used 247 strains collected over several decades in multiple world regions, including the 163 clinical isolates collected prospectively from 2008 to 2017 in France mainland and overseas territories.</jats:p><jats:p>Phylogenetic analysis revealed multiple deep-branching sublineages, grouped into a Mitis lineage strongly associated with diphtheria toxin production, and a<jats:italic>tox</jats:italic>-negative Gravis lineage with few<jats:italic>tox</jats:italic><jats:sup>+</jats:sup>exceptions including the 1990s ex-Soviet Union outbreak strain. The distribution of susceptibility phenotypes allowed proposing ecological cutoffs for most of the 19 agents tested, thereby defining acquired antimicrobial resistance. Penicillin resistance was found in 17.2% of prospective isolates. Four isolates were multidrug resistant (&gt;8 agents), including to penicillin and macrolides. Homologous recombination was frequent (r/m = 5) and horizontal gene transfer contributed to the emergence of antimicrobial resistance in multiple sublineages. Genome-wide association mapping uncovered genetic factors of resistance, including an accessory penicillin-binding protein (PBP2m) located in diverse genomic contexts. Gene<jats:italic>pbp2m</jats:italic>is widespread in other<jats:italic>Corynebacterium</jats

Journal article

Medina-Aguayo FJ, Didelot X, Everitt RG, 2020, Speeding up Inference of Homologous Recombination in Bacteria

<jats:title>Abstract</jats:title><jats:p>Bacteria reproduce clonally but most species recombine frequently, so that the ancestral process is best captured using an ancestral recombination graph. This graph model is often too complex to be used in an inferential setup, but it can be approximated for example by the ClonalOrigin model. Inference in the ClonalOrigin model is performed via a Reversible-Jump Markov Chain Monte Carlo algorithm, which attempts to jointly explore: the recombination rate, the number of recombination events, the departure and arrival points on the clonal genealogy for each recombination event, and the range of genomic sites affected by each recombination event. However, the Reversible-Jump algorithm usually performs poorly due to the complexity of the target distribution since it needs to explore spaces of different dimensions. Recent developments in Bayesian computation methodology have provided ways to improve existing methods and code, but are not well-known outside the statistics community. We show how exploiting one of these new computational methods can lead to faster inference under the ClonalOrigin model.</jats:p>

Journal article

Osnes MN, Didelot X, de Korne-Elenbaas J, Alfsnes K, Brynildsrud OB, Syversen G, Nilsen Ø, de Blasio BF, Caugant DA, Eldholm Vet al., 2020, The sudden emergence of a Neisseria gonorrhoeae strain with reduced susceptibility to extended-spectrum cephalosporins, Norway

<jats:title>Abstract</jats:title><jats:p>The <jats:italic>Neisseria gonorrhoeae</jats:italic> multilocus sequence type (ST) 7827 emerged in dramatic fashion in Norway in the period 2016-2018. Here, we aim to determine what enabled it to establish and spread so quickly. In Norway, ST-7827 isolates were almost exclusively isolated from men. Phylogeographic analyses demonstrated an Asian origin of the ST with multiple importation events to Europe. The ST was uniformly resistant to fluoroquinolones and associated with reduced susceptibility to both azithromycin and the extended-spectrum cephalosporins (ESC) cefixime and ceftriaxone. We identified additional independent events of acquisition of <jats:italic>penA</jats:italic> and <jats:italic>porB</jats:italic> alleles in Europe, associated with further reduction in cefixime and ceftriaxone susceptibility, respectively. Transmission of the ST was largely curbed in Norway in 2019, but our results indicate the existence of a reservoir in Europe. The worrisome drug resistance profile and rapid emergence of ST-7827 calls for close monitoring of the situation.</jats:p>

Journal article

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