May 2019 | Kate

Research overview

Antimicrobial resistance (AMR) is an urgent global public health crisis. Microbial genomics helps us understand the drivers of emergence and transmission of AMR in bacterial populations and there is a need to harness this understanding to create interventions for public health. My group achieves this by combining genomic epidemiology studies of bacteria collected in both high-income and lower-to-middle-income countries, laboratory experimentation and mathematical modelling.

DISEASE AND AMR BURDEN OF SHIGELLA: much disease, few management options
  • Top bacterial cause of moderate-severe diarrhoeal disease in children <5 yrs in South Asia and Sub-saharan Africa1
  • Cause of foodborne illness and traveller’s diarrhoea in high-incomes nations
  • Emerging globally as a sexually transmissible enteric illness (STEI) among men-who-have-sex-with-men (MSM)2
  • One of the WHO top dozen agents for which new antimicrobials are urgently needed3
  • No licensed vaccine for Shigella
SHIGELLA AS A MODEL: highly visible and traceable problem organism

Shigella are members of the Enterobacteriaceae, which includes 3 of the 12 WHO top-dozen AMR pathogens.3 Genomically, Shigella are highly changeable and elaborate AMR in ways relevant to all Enterobacteriaceae, including horizontal gene transfer and point mutations. Unlike many Enterobacteriaceae however, there is little evidence for a significant environmental or animal reservoir for Shigella, making them comparatively easy to track and, as they cause severe disease (dysentery), they are highly-visible in health care systems.

TRACKING AMR Shigella AS AN STEI OF MSM

The occurrence of highly AMR Shigella among MSM:

  • is a public health issue
  • represents a broader crisis of highly AMR-STIs in MSM, including gonorrhoea
  • facilitates the study of Shigella AMR genomics in a dense transmission network with high antimicrobial usage in high-income nation surveillance settings

In a large international collaboration, we identified a Shigella sublineage that is emerging globally (UK, France, Canada, Australia) among MSM and is associated with transmissible AMR (plasmid-borne macrolide resistance) 2. This work was then built on to identify that the resistance plasmid was moving among different sublineages of Shigella transmitting among MSM. Plasmid acquisition drove epidemics of new Shigella sublineages4.

We are currently extending this work in collaboration with PHE by:

1) correlating the transmission behaviour of the plasmid in the laboratory to the public-health level incidence data of different Shigella sublineages and develop models to determine the impact of antimicrobial management strategies to inform stewardship

2) determine whether the microbiota and/or co-infection facilitates AMR transmission among MSM-associated Shigella strains

We are expanding this work through prospective clinical studies in collaboration with PHE HPRUs and the Liverpool Royal and Broadgreen Hospitals Trust and with Public Health England’s through the NIHR-funded Health Protection Research Units, including Drs Claire Jenkins and Tim Dallman.

INFORMING MANAGEMENT OF SHIGELLOSIS IN RESOURCE-POOR REGIONS

MSM-associated Shigella is important and the genomic insights are relevant to less observable disease scenarios, including in LMICs where the greatest disease burden occurs and contributes to broader AMR through travel. Infectious disease studies in LMIC are often complicated by a lack of systematic surveillance. We have previously engaged with existing surveillance networks (such as the foodborne illness transmission network PulseNet Latin America) to create a genomic benchmark for new pathogen databases5.

To continue our work to address the Shigella disease burden in LMIC, we are studying the systematically-collected Shigella isolates from GEMS, a five-year aetiological study on moderate to severe diarrhoeal disease in children <5 years conducted across seven nations in South Asia and SubSaharan Africa 1. The GEMS work is in collaboration with Sharon Tennant at the University of Maryland, Baltimore and Neil Hall at the Earlham Institute in Norwich. We are also studying the genomic epidemiology of Shigella in South Africa in collaboration with the National Centre for Infectious Diseases in South Africa and are part of the BMGF funded Shigella surveillance intitiative Enterics for Global Health. By studying the genome sequences, we will:

  • identify Shigella sublineages most responsible for disease in this key demographic
  • evaluate local and regional antimicrobial treatment guidelines against pathogen AMR signatures
  • work to aid the use of vaccines for Shigella in these regions including: identify relevant variation in existing vaccine candidates; better-characterise phenomena that contribute to vaccine escape; and identify novel vaccine candidates
STUDYING FEATURES EVOLVING IN PARALLEL WITH AMR

Underpinning our understanding the genomic epidemiology of pathogens and AMR is a fundamental understanding of their evolution. Historical isolates of Shigella show targeted gain of AMR and virulence characteristics over time (e.g. this WW1 isolate study)6. We are now seeking other genes with similar temporal signatures to AMR to determine what else contributes to pathogen persistence in populations over time in collaboration with the National Collection of Type Cultures and Tim Blower at the University of Durham. Furthermore, studying convergent evolution of AMR pathogens may highlight precursor changes that accompany the emergence of AMR. This forms the basis of a BBSRC project grant in collaboration with Jamie Hall and UKHSA colleagues.

References
  1. Kotloff et al (2013) Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. The Lancet.
  2. Baker et al (2015) Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. Lancet Infectious Diseases.
  3. World Health Organisation (2018) link
  4. Baker et al (2018) Horizontal antimicrobial resistance transfer drives epidemics of multiple Shigella species. Nature Communications.
  5. Baker et al (2016) Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: Advancing global surveillance of foodborne illnesses. Clinical Microbiology and Infection.
  6. Baker et al (2014) The extant WWI dysentery bacillus NCTC1: a genomic analysis. The Lancet.