title: The genomic epidemiology of antimicrobial resistant sexually transmissible shigellosis
Creators: name: Mason, Lewis
Publisher: name: University of Liverpool Repository
Year: 2025

description: Shigella spp. cause shigellosis, a gastrointestinal illness characterised by severe diarrhoea. Sexually transmissible Shigella species (spp.) are becoming more frequently transmitted and increasingly antimicrobial resistant. My work investigated the genomic epidemiology of Shigella spp. outbreaks among men who have sex with men (MSM) in the context of the broader population, with the overall aim of better predicting, preventing, and treating future outbreaks. Firstly, I aimed to investigate the genomic factors potentially driving the re-emergence of sexually transmissible S. sonnei outbreaks in the early-to-mid 2000s. Then, I investigated the genomic and population dynamics surrounding the re-emergence of S. flexneri 3a in England, post-2015, and urgently responded to the international emergence of extensively drug-resistant (XDR) S. sonnei. Finally, I analysed the empirical treatment of shigellosis by hospitals in England, and combined bacterial genomic data with patient metadata, aiming to suggest effective empirical antimicrobial treatments for use by clinicians, guided by patient demographics.
My work involved the genomic, phylogenetic, and population epidemiological analyses of 3,825 S. sonnei and S. flexneri isolates, from both national and international sources. Phylogenetic and genotypic data from Shigella spp. were combined with patient metadata (date of infection, sex, age group, travel history) to uncover relationships between the isolates, transmission, and genomic and population demographic drivers of newly emergent or re-emerging outbreaks. I also conducted wet-laboratory antimicrobial susceptibility testing to support phenotypic validation.
Collectively, these results suggested that a combination of genomic and epidemiological factors potentially contributed to the emergence and re-emergence of Shigella spp. outbreaks, alongside the urgent need for updated antimicrobial treatment guidelines in the wake of internationally disseminating XDR outbreaks. I found that the re-emergence of sexually transmissible shigellosis in the early-to-mid 2000s outbreaks was driven by a single lineage basal to the internationally dominant S. sonnei lineage, and may have been related to the acquisition of colicin genes, associated with the killing of competitor bacteria. However, the outbreaks may have also been separately driven by distinct genomic factors, owing to the differing plasmid, AMR, and virulence gene profiles. Furthermore, the outbreaks coincide with the timing of the introduction of highly active antiretroviral therapy (HAART) for HIV, which may have influenced changes in patient behaviour, and antimicrobial resistance (AMR) in the gut microbiome. The re-emergence of S. flexneri 3a was also not readily explainable by a major sole genetic change in the clonal replacement, though I observed a conserved loss in the erm(B) and blaTEM-1 AMR genes. There were no significant changes in patient demographic, highlighting the need for further study into the role of host immunity in outbreak re-emergence. I observed that the XDR S. sonnei outbreaks across the UK and internationally were indeed phylogenetically and genomically interlinked. The evolution and success of these XDR isolates were potentially driven by changes in antimicrobial treatment regiments for the STI - gonorrhoea, and the acquisition - by the outbreak isolates - of a highly fit plasmid bearing an Extended Spectrum β-lactamase (ESBL) gene. Finally, I observed that the hospital guidance for the empirical treatment of shigellosis was variable nationally, and that patient demographic data could be used to suggest potential effective empirical treatment options for travel- and sexually-associated shigellosis.
Overall, my work highlights the importance of holistic surveillance for the prediction, prevention, and treatment of emergent and re-emergent Shigella spp. outbreaks genomically (AMR, virulence, colicin, and plasmid profiles) and epidemiologically (demographic, behaviour, and immunity), and with consideration for the gene and plasmid content, and antimicrobial treatment policies of other sexually transmissible infections.