Biology subjects

Langridge, G. C.

Publications and source records attributed to Langridge, G. C..

8 recordsLinked to original sources

bioRxiv2026

Temporal dynamics and acquisition of Shiga toxin subtype stx2a within Shiga toxin-producing Escherichia coli in England, 2016 to 2024

Shiga toxin-producing Escherichia coli (STEC) are an important public health concern due to their association with foodborne gastroenteritis and severe outcomes including haemolytic uraemic syndrome (HUS), particularly linked to the stx2a subtype of the Shiga toxin. We investigated the temporal dynamics and acquisition of stx2a among STEC isolates submitted to the United Kingdom Health Security Agency (UKHSA) between 2016 and 2024. 12,888 whole genome STEC sequences and associated metadata were analysed. 31.9% of STEC isolates harboured stx2a, spanning 78 O serogroups with a marked shift from STEC O157 to non-O157 serogroups over time. STEC O26:H11 and STEC O145:H28 were the primary drivers of observed increases, most commonly associated with stx2a alone or in combination with stx1a. The widespread and increasing presence of stx2a across the STEC population in England highlights an emerging public health risk and demonstrates the value of routine genomic surveillance in monitoring high-severity Shiga toxin subtypes.

genetics↗

bioRxiv2026

Salmonella Genomic Markers for Risk to Food Safety

Foodborne non-typhoidal Salmonella remains a major public health concern, yet many isolates recovered through food surveillance are not associated with human illness. To investigate whether genomic factors influence infection risk, we analysed whole-genome sequencing data from over 900 food and environmental isolates collected through UK Health Security Agency surveillance. Hierarchical clustering and comparative genomics identified distinct lineages associated with clinical cases, which were further contextualised using the global EnteroBase database. By combining pangenome and genome-wide association analyses, we identified distinct lineages within several serovars that differed in their association with human cases. In Salmonella Agona, all clinical isolates belonged to a single lineage carrying a highly conserved 7 kb marker that was absent from low-risk strains and demonstrated strong sensitivity and specificity across global datasets. This marker was located within a prophage closely related to the well-characterised Fels-2 phage and encodes a DNA invertase previously implicated in phase variation, a mechanism that promotes bacterial adaptability. Our findings indicate that infection risk can be structured at the lineage level and associated with mobile genomic elements, particularly prophages, that may contribute to environmental persistence and host adaptation. This work advances genomic surveillance from retrospective linkage towards mechanistic and predictive risk assessment, with direct relevance for supporting risk-based decision-making during outbreak investigations. IMPORTANCENot all strains found in food pose the same risk to human health, yet current surveillance systems generally treat them as equivalent hazards. We analysed over 900 genomes from food and environmental sources and found that human infection risk can be concentrated within specific genetic lineages rather than distributed across an entire serovar. In Salmonella Agona, we identified a highly conserved prophage-associated marker with strong sensitivity and specificity for infection-associated lineages. This marker was located within a prophage related to the well-characterised Fels-2 phage and encoded a DNA invertase previously associated to bacterial adaptation. These findings show how genome sequencing can move beyond outbreak detection to identify lineages with elevated public health relevance. Incorporating such information into surveillance programmes could improve risk-based decision-making, helping public health agencies prioritise investigations and interventions more effectively.

genomics↗

bioRxiv2026

Historical isolates provide insights into the evolution of Acinetobacter baumannii international clone 2 and its resistome

Acinetobacter baumannii remains a pervasive nosocomial pathogen, with international clone 2 (IC2) being the most successful lineage. IC2 is often discussed as a singular entity, and the genomic factors behind its success over other lineages are poorly characterised. This study aimed to track genomic changes occurring around the emergence of IC2 and further determine the within-clone population structure. A set of historical A. baumannii isolates from the 1970s to early 2000s were long-read sequenced and assembled into high-quality chromosomes. These were then used to supplement publicly available A. baumannii genomes, producing a dataset of 1,281 chromosomes derived from isolates collected across six continents. A recombination-free phylogeny was produced and combined with antimicrobial resistance gene (ARG) presence/absence data. Analysis showed that IC2 began to emerge as the dominant lineage around 2005, which coincides with the acquisition of oxa23 and AbGRI3. Further, IC2 can be split into at least four distinct groups. Groups 1, 2, and 3 represent incremental evolution of the A. baumannii chromosome over time, while group 4 represents a separate evolutionary path distinct from the main IC2 lineage, which has recently been isolated at higher frequency. Significance statementCharacterising the evolution and population structure of antimicrobial-resistant bacterial pathogens is of key importance both for epidemiological monitoring and developing approaches to combat infections and their spread. Here, we use a unique collection of historical isolates to show that the major international clone in the WHO priority pathogen Acinetobacter baumannii is comprised of different, independent groups with individual antimicrobial resistance gene compliments. This highlights new areas for research to understand the clinical impact of the different groups and the drivers underlying the evolution and spread of epidemic clones of antimicrobial-resistance bacterial pathogens.

microbiology↗

bioRxiv2025

Plasticity in a bacterial global regulatory switch that drives a shift in antibiotic resistance and virulence

Antibiotic resistance and expression of virulence factors can impact the outcome of infection by Pseudomonas aeruginosa. Pathogenesis is often modelled using the P. aeruginosa PAO1 reference strain but laboratory lineages vary in the sequence and activity of MexT, a global regulator impacting virulence, biofilm formation and ciprofloxacin resistance. We defined the impact of active versus inactive MexT in PAO1 and observed global transcriptomic changes affecting the expression of 900 genes. Phenotyping revealed altered metabolism, antibiotic resistance and virulence - resulting in striking variation across a single model organism. We propose that antibiotic-resistance, introduced during work with the original PAO1 strain, has caused plasticity in mexT that accounts for variation across lineages. To test this, we introduced antibiotic resistance into clinical P. aeruginosa isolates and observed downstream mutations in mexT when selective pressure was removed, supporting the proposed evolutionary pathway. Overall, we have demonstrated the transcriptomic basis of MexT as a phenotypic switch in PAO1 and implicated antibiotic resistance as a cause of downstream changes in mexT in P. aeruginosa. Furthermore, MexS/MexT-regulated efflux is implicated in the antibiotic stress response and virulence, helping identify the mechanisms for rapid phenotypic switching through mexT and confirming that PAO1 is a very different organism compared to most isolates. Improved understanding of the regulatory changes linked to antibiotic resistance is particularly relevant to P. aeruginosa where cycles of antibiotic treatment are common.

microbiology↗

bioRxiv2024

Genomic Epidemiology of SARS-CoV-2 in Norfolk, UK, March 2020 - December 2022

BackgroundIn the UK, the COVID-19 Genomics UK Consortium (COG-UK) established a real time national genomic surveillance system during the COVID-19 pandemic, producing centralised data for monitoring SARS-CoV-2. As a COG-UK partner, Quadram Institute Bioscience (QIB) in Norfolk sequenced over 87,000 SARS-CoV-2 genomes, contributing to the region becoming densely sequenced. Retrospective analysis of SARS-CoV-2 lineage dynamics in this region may contribute to preparedness for future pandemics. Methods29,406 SARS-CoV-2 whole genome sequences and corresponding metadata from Norfolk were extracted from the COG-UK dataset, sampled between March 2020 and December 2022, representing 9.9% of regional COVID-19 cases. Sequences were lineage typed using Pangolin, and subsequent lineage analysis carried out in R using RStudio and related packages, including graphical analysis using ggplot2. Results401 global lineages were identified, with 69.8% appearing more than once and 31.2% over ten times. Temporal clustering identified six lineage communities based on first lineage emergence. Alpha, Delta, and Omicron variants of concern (VOC) accounted for 8.6%, 34.9% and 48.5% of sequences respectively. These formed four regional epidemic waves alongside the remaining lineages which appeared in the early pandemic prior to VOC designation and were termed pre-VOC lineages. Regional comparison highlighted variability in VOC epidemic wave dates dependent on location. ConclusionThis study is the first to assess SARS-CoV-2 diversity in Norfolk across a large timescale within the COVID-19 pandemic. SARS-CoV-2 was both highly diverse and dynamic throughout the Norfolk region between March 2020 - December 2022, with a strong VOC presence within the latter two thirds of the study period. The study also displays the utility of incorporating genomic epidemiological methods into pandemic response. Data summaryThe COG-UK collection of SARS-CoV-2 sequences and metadata are available for public download on their archive website under the Latest sequence data heading . Sequence names for all sequences used from this dataset alongside GISAID accession numbers where present are available in Supplementary Table 1. Impact statementWe extracted 29,406 regional Norfolk based SARS-CoV-2 sequences from the COG-UK SARS-CoV-2 dataset and revealed significant regional diversity and dynamic emergence of variant of concern (VOC) epidemic waves - spanning Alpha, Delta and Omicron lineages. We also applied statistical modelling to complement genomic methodology, with temporal clustering of significant first lineage emergences chronologically matching VOC waves and subwaves. The study highlights the importance of integration of genomic epidemiology into public health strategies for pandemic response, and the utility of using this data for retrospective research.

genomics↗

bioRxiv2024

From Acute to Persistent Infection: Revealing Phylogenomic Variations in Salmonella Agona

BackgroundSalmonella enterica serovar Agona (S. Agona) has been increasingly recognised as a prominent cause of gastroenteritis. This serovar is a strong biofilm former that can undergo genome rearrangement and enter a viable but non-culturable state whilst remaining metabolically active. Similar strategies are employed by S. Typhi, the cause of typhoid fever, during human infection, which are believed to assist with the transition from acute infection to chronic carriage. Here we report S. Agonas ability to persist in people and examine factors that might be contributing to chronic carriage. MethodsA review of 2,233 S. Agona isolates from UK infections (2004-2020) and associated carriage was undertaken, in which 1,155 had short-read sequencing data available. A subset of 207 isolates was selected from different stages of acute and persistent infections within individual patients. The subset underwent long-read sequencing and genome structure (GS) analysis, as well as phenotyping assays including carbon source utilisation and biofilm formation. Associations between genotypes and phenotypes were investigated to compare acute infections to those which progress to chronic. ResultsGS analysis revealed the conserved arrangement GS1.0 in 195 isolates, and 8 additional GSs in 12 isolates. These rearranged isolates were typically associated with early, convalescent carriage (3 weeks - 3 months). We also identified an increase in SNP variation during this period of infection. ConclusionWe believe this increase in genome-scale and SNP variation reflects a population expansion after acute S. Agona infection, potentially reflecting an immune evasion mechanism which enables persistent infection to become established.

genomics↗

bioRxiv2022

Impact of Salmonella genome rearrangement on gene expression

In addition to nucleotide variation, many bacteria also undergo changes at a much larger scale via rearrangement of their genome structure around long repeat sequences. These rearrangements result in genome fragments shifting position and/or orientation in the genome without necessarily affecting the underlying nucleotide sequence. To date, scalable techniques have not been applied to genome structure (GS) identification, so it remains unclear how extensive this variation is and the extent of its impact upon gene expression. However, the emergence of multiplexed, long-read sequencing overcomes the scale problem, as reads of several thousand bases are routinely produced that can span long repeat sequences to identify the flanking chromosomal DNA, allowing GS identification. Genome rearrangements were generated in Salmonella enterica serovar Typhi through long-term culture at ambient temperature. Colonies with rearrangements were identified via long-range PCR and subjected to long-read nanopore sequencing to confirm genome variation. Four rearrangements were investigated for differential gene expression using transcriptomics. All isolates with changes in genome arrangement relative to the parent strain were accompanied by changes in gene expression. Rearrangements with similar fragment movements demonstrated similar changes in gene expression. The most extreme rearrangement caused a large imbalance between the origin and terminus of replication and was associated with differential gene expression as a factor of distance moved towards or away from the origin of replication. Genome structure variation may provide a mechanism through which bacteria can quickly adapt to new environments and warrants routine assessment alongside traditional nucleotide level measures of variation.

genomics↗

bioRxiv2021

Known mechanisms account for less than half of antimicrobial resistance in a diverse collection of non-aureus staphylococci.

IntroductionNon-aureus staphylococci (NAS) are implicated in many healthcare-acquired infections and an understanding of the genetics of antimicrobial resistance in NAS is important in relation to both clinical intervention and the role of NAS as a reservoir of resistance genes. Gap statementThe burden of antimicrobial resistance in NAS, particularly to clinically relevant antimicrobials, is under recognised. MethodologyWe sourced 394 NAS isolates from clinical samples, healthy human volunteers, animals and type cultures and subjected them to agar dilution susceptibility testing against eight antimicrobials. Cefoxitin was used to screen for methicillin resistance in S. aureus, as it stimulates expression of mecA. We performed whole genome sequencing on 366 isolates and analysed these genotypically for the presence of genetic mechanisms responsible for the phenotypic levels of reduced antimicrobial susceptibility. ResultsWe observed 175 sequenced isolates with a minimum inhibitory concentration (MIC) of at least 4 g/ml to cefoxitin, of which 50% (87/175) did not harbour a known mec homologue. Eight clinical NAS isolates displayed high daptomycin MICs (>4 g/ml), with no known mechanism identified. Differences in MICs against erythromycin were attributable to the presence of different resistance genes (msrA and ermC). In total, 49% (193 /394) of isolates displayed reduced susceptibility to three or more of the antimicrobials tested. ConclusionsThe widespread presence of reduced antimicrobial susceptibility in NAS is a concern, with an increased likelihood of (1) harder to treat infections caused directly by NAS, and (2) resistance genes being passed on to other bacteria via horizontal gene transfer, both of which have clinical implications for treatment and management of patients.

microbiology↗