Publications
197 results found
Nimmo C, Ortiz AT, Tan CCS, et al., 2024, Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis., Genome Med, Vol: 16
BACKGROUND: Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. METHODS: We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence. RESULTS: We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation. CONCLUSIONS: The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.
Wan Y, Myall AC, Boonyasiri A, et al., 2024, Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes., J Infect Dis
BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.
Carson J, Keeling M, Wyllie D, et al., 2024, Inference of Infectious Disease Transmission through a Relaxed Bottleneck Using Multiple Genomes Per Host., Mol Biol Evol, Vol: 41
In recent times, pathogen genome sequencing has become increasingly used to investigate infectious disease outbreaks. When genomic data is sampled densely enough amongst infected individuals, it can help resolve who infected whom. However, transmission analysis cannot rely solely on a phylogeny of the genomes but must account for the within-host evolution of the pathogen, which blurs the relationship between phylogenetic and transmission trees. When only a single genome is sampled for each host, the uncertainty about who infected whom can be quite high. Consequently, transmission analysis based on multiple genomes of the same pathogen per host has a clear potential for delivering more precise results, even though it is more laborious to achieve. Here, we present a new methodology that can use any number of genomes sampled from a set of individuals to reconstruct their transmission network. Furthermore, we remove the need for the assumption of a complete transmission bottleneck. We use simulated data to show that our method becomes more accurate as more genomes per host are provided, and that it can infer key infectious disease parameters such as the size of the transmission bottleneck, within-host growth rate, basic reproduction number, and sampling fraction. We demonstrate the usefulness of our method in applications to real datasets from an outbreak of Pseudomonas aeruginosa amongst cystic fibrosis patients and a nosocomial outbreak of Klebsiella pneumoniae.
Yenew B, Ghodousi A, Diriba G, et al., 2023, A smooth tubercle bacillus from Ethiopia phylogenetically close to the Mycobacterium tuberculosis complex., Nat Commun, Vol: 14
The Mycobacterium tuberculosis complex (MTBC) includes several human- and animal-adapted pathogens. It is thought to have originated in East Africa from a recombinogenic Mycobacterium canettii-like ancestral pool. Here, we describe the discovery of a clinical tuberculosis strain isolated in Ethiopia that shares archetypal phenotypic and genomic features of M. canettii strains, but represents a phylogenetic branch much closer to the MTBC clade than to the M. canettii strains. Analysis of genomic traces of horizontal gene transfer in this isolate and previously identified M. canettii strains indicates a persistent albeit decreased recombinogenic lifestyle near the emergence of the MTBC. Our findings support that the MTBC emergence from its putative free-living M. canettii-like progenitor is evolutionarily very recent, and suggest the existence of a continuum of further extant derivatives from ancestral stages, close to the root of the MTBC, along the Great Rift Valley.
Torres Ortiz A, Kendall M, Storey N, et al., 2023, Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks., Elife, Vol: 12
Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low-frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.
Helekal D, Keeling M, Grad YH, et al., 2023, Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 20, ISSN: 1742-5689
Esquivel Gomez LR, Savin C, Andrianaivoarimanana V, et al., 2023, Phylogenetic analysis of the origin and spread of plague in Madagascar, PLOS NEGLECTED TROPICAL DISEASES, Vol: 17, ISSN: 1935-2735
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- Citations: 1
Dingle KE, Freeman J, Didelot X, et al., 2023, Penicillin Binding Protein Substitutions Cooccur with Fluoroquinolone Resistance in Epidemic Lineages of Multidrug-Resistant Clostridioides difficile, MBIO, ISSN: 2150-7511
Kendall M, Tsallis D, Wymant C, et al., 2023, Epidemiological impacts of the NHS COVID-19 app in England and Wales throughout its first year, NATURE COMMUNICATIONS, Vol: 14
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- Citations: 3
Mughal SR, Niazi SA, Do T, et al., 2023, Genomic Diversity among <i>Actinomyces naeslundii</i> Strains and Closely Related Species, MICROORGANISMS, Vol: 11
Abdel-Glil MY, Hotzel H, Tomaso H, et al., 2023, Genomic epidemiology of <i>Campylobacter fetus</i> subsp. <i>venerealis</i> from Germany, FRONTIERS IN VETERINARY SCIENCE, Vol: 9
Didelot X, Helekal D, Kendall M, et al., 2023, Distinguishing imported cases from locally acquired cases within a geographically limited genomic sample of an infectious disease, BIOINFORMATICS, Vol: 39, ISSN: 1367-4803
Didelot X, Franceschi V, Frost SDW, et al., 2023, Model design for nonparametric phylodynamic inference and applications to pathogen surveillance, Virus Evolution, Vol: 9, ISSN: 2057-1577
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 nonparametric 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 nonparametric inference of effective population size is well-developed in the Bayesian setting, but here we develop a frequentist approach based on nonparametric 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. Our methodology is implemented in a new R package entitled mlesky. We demonstrate the flexibility and speed of this approach in a series of simulation experiments and apply the methodology to a dataset of HIV-1 in the USA. 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.
Moore MP, Laager M, Ribeca P, et al., 2022, <i>KmerAperture</i>: Retaining<i>k</i>-mer synteny for alignment-free extraction of core and accessory differences between bacterial genomes
<jats:title>ABSTRACT</jats:title><jats:p>By decomposing genome sequences into<jats:italic>k</jats:italic>-mers, it is possible to estimate genome differences without alignment. Techniques such as<jats:italic>k-</jats:italic>mer minimisers (MinHash), have been developed and are often accurate approximations of distances based on full<jats:italic>k</jats:italic>-mer sets. These and other alignment-free methods avoid the large temporal and computational expense of alignment or mapping. However, these<jats:italic>k</jats:italic>-mer set comparisons are not entirely accurate within-species and can be completely inaccurate within-lineage. This is due, in part, to their inability to distinguish core polymorphism from accessory differences. Here we present a new approach,<jats:italic>KmerAperture</jats:italic>, which uses information on the<jats:italic>k</jats:italic>-mer relative genomic positions to determine the type of polymorphism causing differences in<jats:italic>k</jats:italic>-mer presence and absence between pairs of genomes. Single SNPs are expected to result in contiguous series of relative unique<jats:italic>k</jats:italic>-mers of length<jats:italic>L</jats:italic>=<jats:italic>k</jats:italic>. On the other hand, series of length<jats:italic>L</jats:italic>><jats:italic>k</jats:italic>may be caused by accessory differences of length<jats:italic>L</jats:italic>-<jats:italic>k</jats:italic>+1; when the start and end of the sequence are contiguous with homologous sequence. Alternatively, they may be caused by multiple SNPs within<jats:italic>k</jats:italic>bp from each other and<jats:italic>KmerAperture</jats:italic>can determine whether that is the case. To demonstrate use cases<jats:italic>KmerAperture</jats:italic>was benchmarked using
Didelot X, Parkhill J, 2022, A scalable analytical approach from bacterial genomes to epidemiology, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 377, ISSN: 0962-8436
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- Citations: 5
Carson J, Ledda A, Ferretti L, et al., 2022, The bounded coalescent model: Conditioning a genealogy on a minimum root date, JOURNAL OF THEORETICAL BIOLOGY, Vol: 548, ISSN: 0022-5193
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- Citations: 1
Didelot X, Evans CM, 2022, London parochial burial records from 1563 to 1665 indicate higher plague death rates for males than females: Some possible demographic and social explanations, PLOS ONE, Vol: 17, ISSN: 1932-6203
Didelot X, Helekal D, Kendall M, et al., 2022, Distinguishing imported cases from locally acquired cases within a geographically limited genomic sample of an infectious disease
<jats:title>ABSTRACT</jats:title><jats:p>The ability to distinguish imported cases from locally acquired cases has important consequences for the selection of public health control strategies. Genomic data can be useful for this, for example using a phylogeographic analysis in which genomic data from multiple locations is compared to determine likely migration events between locations. However, these methods typically require good samples of genomes from all locations, which is rarely available. Here we propose an alternative approach that only uses genomic data from a location of interest. By comparing each new case with previous cases from the same location we are able to detect imported cases, as they have a different genealogical distribution than that of locally acquired cases. We show that, when variations in the size of the local population are accounted for, our method has good sensitivity and excellent specificity for the detection of imports. We applied our method to data simulated under the structured coalescent model and demonstrate relatively good performance even when the local population has the same size as the external population. Finally, we applied our method to several recent genomic datasets from both bacterial and viral pathogens, and show that it can, in a matter of seconds or minutes, deliver important insights on the number of imports to a geographically limited sample of a pathogen population.</jats:p>
Willgert K, Didelot X, Surendran-Nair M, et al., 2022, Transmission history of SARS-CoV-2 in humans and white-tailed deer, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
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- Citations: 3
Didelot X, Ribeca P, 2022, KPop: Accurate, assembly-free, and scalable comparative analysis of microbial genomes
<jats:title>Abstract</jats:title><jats:p>The recent explosion in the amount of available sequencing data challenges existing analysis techniques. Here we introduce KPop, a novel versatile method based on full<jats:italic>k</jats:italic>-mer spectra and dataset-specific transformations, through which thousands of assembled or unassembled microbial genomes can be quickly compared. Unlike minimizer-based methods that produce distances and have lower resolution, KPop is able to accurately map sequences onto a low-dimensional space. Extensive validation on simulated and real-life viral and bacterial datasets shows that KPop can correctly separate sequences at both species and sub-species levels even when the overall genomic diversity is low. KPop also rapidly identifies related sequences and systematically outperforms minimizer-based methods. KPop’s code is open-source and available on GitHub at<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/PaoloRibeca/KPop">https://github.com/PaoloRibeca/KPop</jats:ext-link>.</jats:p>
Ortiz AT, Kendall M, Storey N, et al., 2022, Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks., bioRxiv
Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches to reconstruct outbreaks exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is stable among repeated serial samples from the same host, is transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.
Volk D, Yang-Turner F, Didelot X, et al., 2022, Catwalk: identifying closely related sequences in large microbial sequence databases, MICROBIAL GENOMICS, Vol: 8, ISSN: 2057-5858
Dingle KE, Freeman J, Didelot X, et al., 2022, Penicillin Binding Protein Substitutions Co-occur with Fluoroquinolone Resistance in ‘Epidemic’ Lineages of Multi Drug-Resistant <i>Clostridioides difficile</i>
<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Clostridioides difficile</jats:italic> remains a key cause of healthcare-associated infection, with multi-drug-resistant (MDR) lineages causing high mortality (≥20%) outbreaks. Cephalosporin treatment is a long-established risk factor, and antimicrobial stewardship a key control. A mechanism underlying raised cephalosporin MICs has not been identified in <jats:italic>C. difficile</jats:italic>, but among other species resistance is often acquired <jats:italic>via</jats:italic> amino acid substitutions in cell wall transpeptidases (penicillin binding proteins, PBPs). Here, we investigated five <jats:italic>C. difficile</jats:italic> transpeptidases (PBP1-5) for recent substitutions. Previously published genome assemblies (n=7096) were obtained, representing sixteen geographically widespread lineages, including healthcare-associated MDR ST1(027), ST3(001) and ST17(018). Recent amino acid substitutions were found within PBP1 (n=50) and PBP3 (n=48), ranging from 1-10 substitutions per genome. β-lactam MICs were measured for closely related pairs of wild-type and PBP substituted isolates separated by 20-273 SNPs. Recombination-corrected, dated phylogenies were constructed to date substitution acquisition. Key substitutions such as PBP3 V497L and PBP1 T674I/N/V emerged independently across multiple lineages. They were associated with extremely high cephalosporin MICs; 1-4 doubling dilutions >wild-type up to ≤1506μg/ml. Substitution patterns varied by lineage and clade, showed geographic structure, and notably occurred post-1990, coincident with the acquisition of <jats:italic>gyrA</jats:italic>/<jats:italic>B</jats:italic> substitutions conferring fluoroquinolone resistance. In conclusion, recent PBP1 and PBP3 substitutions are associated with raised cephalosporin MICs in <jats:italic>C. difficile</ja
Ledda A, Cummins M, Shaw LP, et al., 2022, Hospital outbreak of carbapenem-resistant Enterobacterales associated with a bla OXA-48 plasmid carried mostly by Escherichia coli ST399, Microbial Genomics, Vol: 8, ISSN: 2057-5858
A hospital outbreak of carbapenem-resistant Enterobacterales was detected by routine surveillance. Whole genome sequencing and subsequent analysis revealed a conserved promiscuous blaOXA-48 carrying plasmid as the defining factor within this outbreak. Four different species of Enterobacterales were involved in the outbreak. Escherichia coli ST399 accounted for 35 of all the 55 isolates. Comparative genomics analysis using publicly available E. coli ST399 genomes showed that the outbreak E. coli ST399 isolates formed a unique clade. We developed a mathematical model of pOXA-48-like plasmid transmission between host lineages and used it to estimate its conjugation rate, giving a lower bound of 0.23 conjugation events per lineage per year. Our analysis suggests that co-evolution between the pOXA-48-like plasmid and E. coli ST399 could have played a role in the outbreak. This is the first study to report carbapenem-resistant E. coli ST399 carrying blaOXA-48 as the main cause of a plasmid-borne outbreak within a hospital setting. Our findings suggest complementary roles for both plasmid conjugation and clonal expansion in the emergence of this outbreak.
Whittles L, Didelot X, White P, 2022, Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis, Lancet Infectious Diseases, Vol: 22, ISSN: 1473-3099
Background Gonorrhoea is a rapidly-growing public health threat, with rising incidence andincreasing drug-resistance. Evidence that meningococcal vaccines MeNZB and 4CMenB offerprotection has created interest in using 4CMenB against gonorrhoea and in developinggonorrhoea-specific vaccines, but cost-effectiveness and how efficacy and duration of protectionaffect a vaccine’s value have not been assessed.Methods We developed an integrated transmission-dynamic health-economic model, calibratedusing Bayesian methods to surveillance data (GUMCAD: Genitourinary Medicine Clinic ActivityDataset, and GRASP: Gonococcal Resistance to Antimicrobials Surveillance Programme) on menwho-have-sex-with-men (MSM) in England. We considered vaccination of MSM from theperspective of sexual health clinics (with and without vaccination of all adolescents in schools),comparing three realistic approaches to targeting: vaccination-on-attendance for testing;vaccination-on-diagnosis with gonorrhoea; or vaccination-according-to-risk, offered to patientsdiagnosed with gonorrhoea plus those testing negative who report high numbers of partners(>5p.a.). We varied vaccine uptake (0·5-2× HPV vaccine uptake); efficacy (1-100%) and durationof protection (1-20 years); future epidemic trajectories (current trends stabilising, or continuing);and the time-horizon considered (10&20 years).Findings Adolescent vaccination has little impact with only 1·7%p.a. vaccinated. Vaccinationaccording-to-risk combines high impact and efficiency: even under conservative assumptions4CMenB would likely be cost-saving in use against gonorrhoea in MSM in England at the currentNHS price for use against infant meningitis, averting an estimated mean 110,200(95%CrI:36,500-223,600) cases, gaining 100·3(31·0-215·8) QALYs, and saving £7·9M(£0·0M-£20·5M) over 10years. A hypothetical gonorrhoea vaccine’s value is increased more by improvi
Wang L, Didelot X, Bi Y, et al., 2022, SARS-CoV-2 transmissibility compared between variants of concern and vaccination status, BRIEFINGS IN BIOINFORMATICS, Vol: 23, ISSN: 1467-5463
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- Citations: 1
Larsen J, Raisen CL, Ba X, et al., 2022, Emergence of methicillin resistance predates the clinical use of antibiotics, NATURE, Vol: 602, Pages: 135-+, ISSN: 0028-0836
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- Citations: 10
Fountain-Jones NM, Kraberger S, Gagne RB, et al., 2022, Hunting alters viral transmission and evolution in a large carnivore, NATURE ECOLOGY & EVOLUTION, Vol: 6, Pages: 174-+, ISSN: 2397-334X
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- Citations: 5
Carson J, Ledda A, Ferretti L, et al., 2022, The bounded coalescent model: conditioning a genealogy on a minimum root date
<jats:title>Abstract</jats:title><jats:p>The coalescent model represents how individuals sampled from a population may have originated from a last common ancestor. The bounded coalescent model is obtained by conditioning the coalescent model such that the last common ancestor must have existed after a certain date. This conditioned model arises in a variety of applications, such as speciation, horizontal gene transfer or transmission analysis, and yet the bounded coalescent model has not been previously analysed in detail. Here we describe a new algorithm to simulate from this model directly, without resorting to rejection sampling. We show that this direct simulation algorithm is more computationally efficient than the rejection sampling approach. We also show how to calculate the probability of the last common ancestor occurring after a given date, which is required to compute the probability of realisations under the bounded coalescent model. Our results are applicable in both the isochronous (when all samples have the same date) and heterochronous (where samples can have different dates) settings. We explore the effect of setting a bound on the date of the last common ancestor, and show that it affects a number of properties of the resulting phylogenies. All our methods are implemented in a new R package called BoundedCoalescent which is freely available online.</jats:p>
Ortiz AT, Coronel J, Vidal JR, et al., 2021, Genomic signatures of pre-resistance in <i>Mycobacterium tuberculosis</i>, NATURE COMMUNICATIONS, Vol: 12
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- Citations: 18
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