Imperial College London

DrNicholasCroucher

Faculty of MedicineSchool of Public Health

Reader in Bacterial Genomics
 
 
 
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Contact

 

+44 (0)20 7594 3820n.croucher

 
 
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Location

 

1104Building E - Sir Michael UrenWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

106 results found

Croucher NJ, Campo JJ, Le TQ, Pablo JV, Hung C, Teng AA, Turner C, Nosten F, Bentley SD, Liang X, Turner P, Goldblatt Det al., 2024, Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci, Nature Communications, Vol: 15, ISSN: 2041-1723

Streptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals’ responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins’ ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts’ polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.

Journal article

Kwun MJ, Ion A, Oggioni MR, Bentley SD, Croucher NJet al., 2023, Diverse regulatory pathways modulate bet hedging of competence induction in epigenetically-differentiated phase variants of Streptococcus pneumoniae, NUCLEIC ACIDS RESEARCH, ISSN: 0305-1048

Journal article

Horsfield ST, Tonkin-Hill G, Croucher NJ, Lees JAet al., 2023, Accurate and fast graph-based pangenome annotation and clustering with ggCaller., Genome Res, Vol: 33, Pages: 1622-1637

Bacterial genomes differ in both gene content and sequence mutations, which underlie extensive phenotypic diversity, including variation in susceptibility to antimicrobials or vaccine-induced immunity. To identify and quantify important variants, all genes within a population must be predicted, functionally annotated, and clustered, representing the "pangenome." Despite the volume of genome data available, gene prediction and annotation are currently conducted in isolation on individual genomes, which is computationally inefficient and frequently inconsistent across genomes. Here, we introduce the open-source software graph-gene-caller (ggCaller). ggCaller combines gene prediction, functional annotation, and clustering into a single workflow using population-wide de Bruijn graphs, removing redundancy in gene annotation and resulting in more accurate gene predictions and orthologue clustering. We applied ggCaller to simulated and real-world bacterial data sets containing hundreds or thousands of genomes, comparing it to current state-of-the-art tools. ggCaller has considerable speed-ups with equivalent or greater accuracy, particularly with data sets containing complex sources of error, such as assembly contamination or fragmentation. ggCaller is also an important extension to bacterial genome-wide association studies, enabling querying of annotated graphs for functional analyses. We highlight this application by functionally annotating DNA sequences with significant associations to tetracycline and macrolide resistance in Streptococcus pneumoniae, identifying key resistance determinants that were missed when using only a single reference genome. ggCaller is a novel bacterial genome analysis tool with applications in bacterial evolution and epidemiology.

Journal article

Horsfield ST, Croucher NJ, Lees JA, 2023, Accurate and fast graph-based pangenome annotation and clustering with ggCaller

<jats:title>Abstract</jats:title><jats:p>Bacterial genomes differ in both gene content and sequence mutations, which can cause important clinical phenotypic differences such as vaccine escape or antimicrobial resistance. To identify and quantify important variants, all genes within a population must be predicted, functionally annotated and clustered, representing the ‘pangenome’. Despite the volume of genome data available, gene prediction and annotation are currently conducted in isolation on individual genomes, which is computationally inefficient and frequently inconsistent across genomes. Here, we introduce the open-source software graph-gene-caller (ggCaller;<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/samhorsfield96/ggCaller">https://github.com/samhorsfield96/ggCaller</jats:ext-link>). ggCaller combines gene prediction, functional annotation and clustering into a single step using population-wide de Bruijn Graphs, removing redundancy in gene annotation, and resulting in more accurate gene predictions and orthologue clustering. We applied ggCaller to simulated and real-world bacterial genome datasets, comparing it to current state-of-the-art tools. ggCaller is ~50x faster with equivalent or greater accuracy, particularly in datasets with complex sources of error, such as assembly contamination or fragmentation. ggCaller is also an important extension to bacterial genome-wide association studies, enabling querying of annotated graphs for functional analyses. We highlight this application by functionally annotating DNA sequences with significant associations to tetracycline and macrolide resistance in<jats:italic>Streptococcus pneumoniae</jats:italic>, identifying key resistance determinants that were missed when using only a single reference genome. ggCaller is a novel bacterial genome analysis tool with applications

Journal article

Glanville DG, Gazioglu O, Marra M, Tokars VL, Kushnir T, Habtom M, Croucher NJ, Nebenzahl YM, Mondragon A, Yesilkaya H, Ulijasz ATet al., 2023, Pneumococcal capsule expression is controlled through a conserved, distal <i>cis</i>-regulatory element during infection, PLOS PATHOGENS, Vol: 19, ISSN: 1553-7366

Journal article

Croucher N, Kwun MJ, Alexandru I, D'Aeth Jet al., 2022, Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA, Genome Medicine: medicine in the post-genomic era, Vol: 14, ISSN: 1756-994X

Background:The respiratory pathogen Streptococcus pneumoniae (the pneumococcus) is a genetically diverse bacterium associated with over 101 immunologically distinct polysaccharide capsules (serotypes). Polysaccharide conjugate vaccines (PCVs) have successfully eliminated multiple targeted serotypes, yet the mucoid serotype 3 has persisted despite its inclusion in PCV13. This capsule type is predominantly associated with a single globally disseminated strain, GPSC12 (clonal complex 180).Methods:A genomic epidemiology study combined previous surveillance datasets of serotype 3 pneumococci to analyse the population structure, dynamics, and differences in rates of diversification within GPSC12 during the period of PCV introductions. Transcriptomic analyses, whole genome sequencing, mutagenesis, and electron microscopy were used to characterise the phenotypic impact of loci hypothesised to affect this strain’s evolution.Results:GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage ϕOXC141. Prior to the introduction of PCV13, this clade’s composition shifted towards a ϕOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also ϕOXC141-negative, have risen in prevalence. The low in vitro transformation efficiency of a Clade I isolate could not be fully explained by the ~100-fold reduction attributable to the serotype 3 capsule. Accordingly, prophage ϕOXC141 was found to modify csRNA3, a non-coding RNA that inhibits the induction of transformation. This alteration was identified in ~30% of all pneumococci and was particularly common in the unusually clonal serotype 1 GPSC2 strain. RNA-seq and quantitative reverse transcriptase PCR experiments using a genetically tractable pneumococcus demonstrated the altered csRNA3 was more effective at inhibiting production of the competen

Journal article

Tonkin-Hill G, Ling C, Chaguza C, Salter SJ, Hinfonthong P, Nikolaou E, Tate N, Pastusiak A, Turner C, Chewapreecha C, Frost SDW, Corander J, Croucher NJ, Turner P, Bentley SDet al., 2022, Pneumococcal within-host diversity during colonization, transmission and treatment, NATURE MICROBIOLOGY, Vol: 7, Pages: 1791-+, ISSN: 2058-5276

Journal article

Lehtinen S, Croucher NJ, Blanquart F, Fraser Cet al., 2022, Epidemiological dynamics of bacteriocin competition and antibiotic resistance, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 289, ISSN: 0962-8452

Journal article

Chaguza C, Ebruke C, Senghore M, Lo SW, Tientcheu P-E, Gladstone RA, Tonkin-Hill G, Cornick JE, Yang M, Worwui A, McGee L, Breiman RF, Klugman KP, Kadioglu A, Everett DB, Mackenzie G, Croucher NJ, Roca A, Kwambana-Adams BA, Antonio M, Bentley SDet al., 2022, Comparative Genomics of Disease and Carriage Serotype 1 Pneumococci, GENOME BIOLOGY AND EVOLUTION, Vol: 14, ISSN: 1759-6653

Journal article

Stevens EJ, Morse DJ, Bonini D, Duggan S, Brignoli T, Recker M, Lees JA, Croucher NJ, Bentley S, Wilson DJ, Earle SG, Dixon R, Nobbs A, Jenkinson H, van Opijnen T, Thibault D, Wilkinson OJ, Dillingham MS, Carlile S, McLoughlin RM, Massey RCet al., 2022, Targeted control of pneumolysin production by a mobile genetic element in <i>Streptococcus</i> <i>pneumoniae</i>, MICROBIAL GENOMICS, Vol: 8, ISSN: 2057-5858

Journal article

Mallawaarachchi S, Tonkin-Hill G, Croucher NJ, Turner P, Speed D, Corander J, Balding Det al., 2022, Genome-wide association, prediction and heritability in bacteria with application to Streptococcus pneumoniae, NAR Genomics and Bioinformatics, Vol: 4, Pages: 1-11, ISSN: 2631-9268

Whole-genome sequencing has facilitated genome-wide analyses of association, prediction and heritability in many organisms. However, such analyses in bacteria are still in their infancy, being limited by difficulties including genome plasticity and strong population structure. Here we propose a suite of methods including linear mixed models, elastic net and LD-score regression, adapted to bacterial traits using innovations such as frequency-based allele coding, both insertion/deletion and nucleotide testing and heritability partitioning. We compare and validate our methods against the current state-of-art using simulations, and analyse three phenotypes of the major human pathogen Streptococcus pneumoniae, including the first analyses of minimum inhibitory concentrations (MIC) for penicillin and ceftriaxone. We show that the MIC traits are highly heritable with high prediction accuracy, explained by many genetic associations under good population structure control. In ceftriaxone MIC, this is surprising because none of the isolates are resistant as per the inhibition zone criteria. We estimate that half of the heritability of penicillin MIC is explained by a known drug-resistance region, which also contributes a quarter of the ceftriaxone MIC heritability. For the within-host carriage duration phenotype, no associations were observed, but the moderate heritability and prediction accuracy indicate a moderately polygenic trait.

Journal article

Chaguza C, Tonkin-Hill G, Lo SW, Hadfield J, Croucher NJ, Harris SR, Bentley SDet al., 2022, RCandy: an R package for visualizing homologous recombinations in bacterial genomes, BIOINFORMATICS, Vol: 38, Pages: 1450-1451, ISSN: 1367-4803

Journal article

Lochen A, Truscott JE, Croucher NJ, 2022, Analysing pneumococcal invasiveness using Bayesian models of pathogen progression rates, PLOS COMPUTATIONAL BIOLOGY, Vol: 18, ISSN: 1553-734X

Journal article

Wan Y, Mills E, Leung RCY, Vieira A, Zhi X, Croucher NJ, Woodford N, Jauneikaite E, Ellington MJ, Sriskandan Set al., 2021, Alterations in chromosomal genes nfsA, nfsB, and ribE are associated with nitrofurantoin resistance in escherichia coli from the UK, Microbial Genomics, Vol: 7, Pages: 1-19, ISSN: 2057-5858

Antimicrobial resistance in enteric or urinary Escherichia coli is a risk factor for invasive E. coli infections. Due to widespread trimethoprim resistance amongst urinary E. coli and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2014. Nitrofurantoin resistance is reported in <6% urinary E. coli isolates in the UK, however, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify the genetic basis of nitrofurantoin resistance in urinary E. coli isolates collected from north west London and then elucidate resistance-associated genetic alterations in available UK E. coli genomes. As a result, an algorithm was developed to predict nitrofurantoin susceptibility.Deleterious mutations and gene-inactivating insertion sequences in chromosomal nitroreductase genes nfsA and/or nfsB were identified in genomes of nine nitrofurantoin-resistant urinary E. coli isolates, as well as all further 11 E. coli isolates that were experimentally validated to be nitrofurantoin resistant. Eight categories of allelic changes in nfsA, nfsB, and the associated gene ribE were detected in 12,412 E. coli genomes from the UK. Evolutionary analysis of these three genes revealed homoplasic mutations and explained the previously reported order of stepwise mutations. The mobile gene complex oqxAB, which is associated with reduced nitrofurantoin susceptibility, was identified in only one of the 12,412 genomes.In conclusion, mutations and insertion sequences in nfsA and nfsB were leading causes of nitrofurantoin resistance in UK E. coli. As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage E. coli isolates and those from urinary and bloodstream infections should be monitored.

Journal article

Løchen A, Truscott JE, Croucher NJ, 2021, Analysing pneumococcal invasiveness using Bayesian models of pathogen progression rates

<jats:title>Abstract</jats:title><jats:p>The disease burden attributable to opportunistic pathogens depends on their prevalence in asymptomatic colonisation and the rate at which they progress to cause symptomatic disease. Increases in infections caused by commensals can result from the emergence of “hyperinvasive” strains. Such pathogens can be identified through quantifying progression rates using matched samples of typed microbes from disease cases and healthy carriers. This study describes Bayesian models for analysing such datasets, implemented in an RStan package (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/nickjcroucher/progressionEstimation">https://github.com/nickjcroucher/progressionEstimation</jats:ext-link>). The models converged on stable fits that accurately reproduced observations from meta-analyses of <jats:italic>Streptococcus pneumoniae</jats:italic> datasets. The estimates of invasiveness, the progression rate from carriage to invasive disease, in cases per carrier per year correlated strongly with the dimensionless values from meta-analysis of odds ratios when sample sizes were large. At smaller sample sizes, the Bayesian models produced more informative estimates. This identified historically rare but high-risk <jats:italic>S. pneumoniae</jats:italic> serotypes that could be problematic following vaccine-associated disruption of the bacterial population. The package allows for hypothesis testing through model comparisons with Bayes factors. Application to datasets in which strain and serotype information were available for <jats:italic>S. pneumoniae</jats:italic> found significant evidence for within-strain and within-serotype variation in invasiveness. The heterogeneous geographical distribution of these genotypes is therefore likely to contribute to differences in the impac

Journal article

D'Aeth JC, van der Linden MPG, McGee L, De Lencastre H, Turner P, Song J-H, Lo SW, Gladstone RA, Sa-Leao R, Ko KS, Hanage WP, Breiman RF, Beall B, Bentley SD, Croucher NJ, GPS Consortiumet al., 2021, The role of interspecies recombinations in the evolution of antibiotic-resistant pneumococci, eLife, Vol: 10, ISSN: 2050-084X

The evolutionary histories of the antibiotic-resistant Streptococcus pneumoniae lineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1 into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout the S. pneumoniae chromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.

Journal article

Gladstone RA, McNally A, Pontinen AK, Tonkin-Hill G, Lees JA, Skyten K, Cleon F, Christensen MOK, Haldorsen BC, Bye KK, Gammelsrud KW, Hjetland R, Kummel A, Larsen HE, Lindemann PC, Lohr IH, Marvik A, Nilsen E, Noer MT, Simonsen GS, Steinbakk M, Tofteland S, Vattoy M, Bentley SD, Croucher NJ, Parkhill J, Johnsen PJ, Samuelsen O, Corander Jet al., 2021, Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002-17: a nationwide, longitudinal, microbial population genomic study, The Lancet Microbe, Vol: 2, Pages: E331-E341, ISSN: 2666-5247

BackgroundThe clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology.MethodsThis was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011.FindingsOf the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-n

Journal article

Croucher N, Harrow G, Lees J, Hanage W, Lipsitch M, Corander J, Colijn Cet al., 2021, Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures, The ISME Journal: multidisciplinary journal of microbial ecology, Vol: 15, Pages: 1523-1538, ISSN: 1751-7362

Streptococcus pneumoniae can be divided into many strains, each a distinct set of isolates sharing similar core and accessorygenomes, which co-circulate within the same hosts. Previous analyses suggested the short-term vaccine-associated dynamicsof S. pneumoniae strains may be mediated through multi-locus negative frequency-dependent selection (NFDS), whichmaintains accessory loci at equilibrium frequencies. Long-term simulations demonstrated NFDS stabilised clonally-evolvingmulti-strain populations through preventing the loss of variation through drift, based on polymorphism frequencies,pairwise genetic distances and phylogenies. However, allowing symmetrical recombination between isolates evolving undermulti-locus NFDS generated unstructured populations of diverse genotypes. Replication of the observed data improvedwhen multi-locus NFDS was combined with recombination that was instead asymmetrical, favouring deletion of accessoryloci over insertion. This combination separated populations into strains through outbreeding depression, resulting fromrecombinants with reduced accessory genomes having lower fitness than their parental genotypes. Although simplisticmodelling of recombination likely limited these simulations’ ability to maintain some properties of genomic data asaccurately as those lacking recombination, the combination of asymmetrical recombination and multi-locus NFDS couldrestore multi-strain population structures from randomised initial populations. As many bacteria inhibit insertions into theirchromosomes, this combination may commonly underlie the co-existence of strains within a niche.

Journal article

Zamudio R, Haigh RD, Ralph JD, Croix MDS, Tasara T, Zurfluh K, Kwun MJ, Millard AD, Bentley SD, Croucher NJ, Stephan R, Oggioni MRet al., 2020, Lineage-specific evolution and gene flow in<i>Listeria monocytogenes</i>are independent of bacteriophages, ENVIRONMENTAL MICROBIOLOGY, Vol: 22, Pages: 5058-5072, ISSN: 1462-2912

Journal article

Lochen A, Croucher N, Anderson R, 2020, Divergent serotype replacement trends and increasing diversity in pneumococcal disease in high income settings reduce the benefit of expanding vaccine valency, Scientific Reports, Vol: 10, ISSN: 2045-2322

Streptococcus pneumoniae is a significant cause of otitis media, pneumonia, and meningitis. Only seven of the approximately 100 serotypes were initially included in the pneumococcal conjugate vaccine (PCV) in 2000 before it was expanded in subsequent years. Although the invasive pneumococcal disease (IPD) incidence due to vaccine serotypes (VT) has declined, partial replacement by non-vaccine serotypes (NVT) was observed following widespread vaccine uptake. We conducted a trend analysis assembling all the available evidence for PCV impact on European, North American and Australian national IPD. Significant effectiveness against VT IPD in infants was observed, although the impact on national IPD incidence varied internationally due to serotype replacement. Currently, NVT serotypes 8, 9N, 15A and 23B are increasing in the countries assessed, although a variety of other NVTs are affecting each country and age group. Despite these common emerging serotypes, there has not been a dominant IPD serotype post-vaccination as there was pre-vaccination (serotype 14) or post-PCV7 (serotype 19A), suggesting that future vaccines with additional serotypes will be less effective at targeting and reducing IPD in global populations than previous PCVs. The rise of diverse NVTs in all settings’ top-ranked IPD-causing serotypes emphasizes the urgent need for surveillance data on serotype distribution and serotype-specific invasiveness post-vaccination to facilitate decision making concerning both expanding current vaccination programmes and increasing vaccine valency.

Journal article

Azarian T, Martinez PP, Arnold BJ, Qiu X, Grant LR, Corander J, Fraser C, Croucher NJ, Hammitt LL, Reid R, Santosham M, Weatherholtz RC, Bentley SD, O'Brien KL, Lipsitch M, Hanage WPet al., 2020, Frequency-dependent selection can forecast evolution in <i>Streptococcus pneumoniae</i>, PLOS BIOLOGY, Vol: 18, ISSN: 1544-9173

Journal article

Harrow GL, Lees JA, Hanage WP, Lipsitch M, Corander J, Colijn C, Croucher NJet al., 2020, Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures

<jats:title>Abstract</jats:title><jats:p><jats:italic>Streptococcus pneumoniae</jats:italic>can be split into multiple strains, each with a characteristic combination of core and accessory genome variation, able to co-circulate and compete within the same hosts. Previous analyses of epidemiological datasets suggested the short-term vaccine-associated dynamics of<jats:italic>S. pneumoniae</jats:italic>strains may be mediated through multi-locus negative frequency-dependent selection (NFDS), acting to maintain accessory loci at equilibrium frequencies. To test whether this model could explain how such multi-strain populations were generated, it was modified to incorporate recombination. The outputs of simulations featuring symmetrical recombination were compared with genomic data on locus frequencies and distributions between genotypes, pairwise genetic distances and tree shape. These demonstrated NFDS prevented the loss of variation through neutral drift, but generated unstructured populations of diverse isolates. Making recombination asymmetrical, favouring deletion of accessory loci over insertion, alongside multi-locus NFDS significantly improved the fit to genomic data. In a population at equilibrium, structuring into multiple strains was stable due to outbreeding depression, resulting from recombinants with reduced accessory genomes having lower fitness than their parental genotypes. As many bacteria inhibit the integration of insertions into their chromosomes, this combination of asymmetrical recombination and multi-locus NFDS may underlie the co-existence of strains within a single ecological niche.</jats:p>

Working paper

Lehtinen S, Chewapreecha C, Lees J, Hanage WP, Lipsitch M, Croucher NJ, Bentley SD, Turner P, Fraser C, Mostowy RJet al., 2020, Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in <i>Streptococcus pneumoniae</i>, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548

Journal article

Gladstone RA, Lo SW, Goater R, Yeats C, Taylor B, Hadfield J, Lees JA, Croucher NJ, van Tonder AJ, Bentley LJ, Quah FX, Blaschke AJ, Pershing NL, Byington CL, Balaji V, Hryniewicz W, Sigauque B, Ravikumar KL, Almeida SCG, Ochoa TJ, Ho PL, du Plessis M, Ndlangisa KM, Cornick JE, Kwambana-Adams B, Benisty R, Nzenze SA, Madhi SA, Hawkins PA, Pollard AJ, Everett DB, Antonio M, Dagan R, Klugman KP, von Gottberg A, Metcalf BJ, Li Y, Beall BW, McGee L, Breiman RF, Aanensen DM, Bentley SDet al., 2020, Visualizing variation within Global Pneumococcal Sequence Clusters (GPSCs) and country population snapshots to contextualize pneumococcal isolates, MICROBIAL GENOMICS, Vol: 6, ISSN: 2057-5858

Journal article

Colijn C, Corander J, Croucher NJ, 2020, Designing ecologically optimized pneumococcal vaccines using population genomics, Nature Microbiology, Vol: 5, Pages: 473-485, ISSN: 2058-5276

Streptococcus pneumoniae (the pneumococcus) is a common nasopharyngeal commensal that can cause invasive pneumococcal disease (IPD). Each component of current protein–polysaccharide conjugate vaccines (PCVs) generally induces immunity specific to one of the approximately 100 pneumococcal serotypes, and typically eliminates it from carriage and IPD through herd immunity. Overall carriage rates remain stable owing to replacement by non-PCV serotypes. Consequently, the net change in IPD incidence is determined by the relative invasiveness of the pre- and post-PCV-carried pneumococcal populations. In the present study, we identified PCVs expected to minimize the post-vaccine IPD burden by applying Bayesian optimization to an ecological model of serotype replacement that integrated epidemiological and genomic data. We compared optimal formulations for reducing infant-only or population-wide IPD, and identified potential benefits to including non-conserved pneumococcal carrier proteins. Vaccines were also devised to minimize IPD resistant to antibiotic treatment, despite the ecological model assuming that resistance levels in the carried population would be preserved. We found that expanding infant-administered PCV valency is likely to result in diminishing returns, and that complementary pairs of infant- and adult-administered vaccines could be a superior strategy. PCV performance was highly dependent on the circulating pneumococcal population, further highlighting the advantages of a diversity of anti-pneumococcal vaccination strategies.

Journal article

Pensar J, Puranen S, Arnold B, MacAlasdair N, Kuronen J, Tonkin-Hill G, Pesonen M, Xu Y, Sipola A, Sanchez-Buso L, Lees JA, Chewapreechi C, Bentley SD, Harris SR, Parkhill J, Croucher NJ, Corander Jet al., 2019, Genome-wide epistasis and co-selection study using mutual information, NUCLEIC ACIDS RESEARCH, Vol: 47, ISSN: 0305-1048

Journal article

Dewe TCM, D'Aetht JC, Croucher NJ, 2019, Genomic epidemiology of penicillin-non-susceptible Streptococcus pneumoniae, Microbial Genomics, Vol: 5, Pages: 1-8, ISSN: 2057-5858

Penicillin-non-susceptible Streptococcus pneumoniae (PNSP) were first detected in the 1960s, and are now common worldwide, predominantly through the international spread of a limited number of strains. Extant PNSP are characterized by mosaic pbp2x, pbp2b and pbp1a genes generated by interspecies recombinations, with the extent of these alterations determining the range and concentrations of β-lactams to which the genotype is non-susceptible. The complexity of the genetics underlying these phenotypes has been the subject of both molecular microbiology and genome-wide association and epistasis analyses. Such studies can aid our understanding of PNSP evolution and help improve the already highly-performing bioinformatic methods capable of identifying PNSP from genomic surveillance data.

Journal article

Furi L, Crawford LA, Rangel-Pineros G, Manso AS, Croix MDS, Haigh RD, Kwun MJ, Fjelland KE, Gilfillan GD, Bentley SD, Croucher NJ, Clokie MR, Oggioni MRet al., 2019, Methylation Warfare: Interaction of Pneumococcal Bacteriophages with Their Host, JOURNAL OF BACTERIOLOGY, Vol: 201, ISSN: 0021-9193

Journal article

Kwun M, Oggioni MR, Bentley SD, Fraser C, Croucher Net al., 2019, Synergistic activity of mobile genetic element defences in Streptococcus pneumoniae, Genes, Vol: 10, ISSN: 2073-4425

A diverse set of mobile genetic elements (MGEs) transmit between Streptococcus pneumoniae cells, but many isolates remain uninfected. The best-characterised defences against horizontal transmission of MGEs are restriction-modification systems (RMSs), of which there are two phase-variable examples in S. pneumoniae. Additionally, the transformation machinery has been proposed to limit vertical transmission of chromosomally integrated MGEs. This work describes how these mechanisms can act in concert. Experimental data demonstrate RMS phase variation occurs at a sub-maximal rate. Simulations suggest this may be optimal if MGEs are sometimes vertically inherited, as it reduces the probability that an infected cell will switch between RMS variants while the MGE is invading the population, and thereby undermine the restriction barrier. Such vertically inherited MGEs can be deleted by transformation. The lack of between-strain transformation hotspots at known prophage att sites suggests transformation cannot remove an MGE from a strain in which it is fixed. However, simulations confirmed that transformation was nevertheless effective at preventing the spread of MGEs into a previously uninfected cell population, if a recombination barrier existed between co-colonising strains. Further simulations combining these effects of phase variable RMSs and transformation found they synergistically inhibited MGEs spreading, through limiting both vertical and horizontal transmission.

Journal article

Nasher F, Kwun MJ, Croucher NJ, Heller M, Hathaway LJet al., 2019, Peptide Occurring in Enterobacteriaceae Triggers <i>Streptococcus pneumoniae</i> Cell Death, FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, Vol: 9, ISSN: 2235-2988

Journal article

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