The impact of Host restriction of Escherichia coli on Transmission dynamics and spread of antimicrobial Resistance

The occurrence of antimicrobial resistance (AMR) is rapidly increasing worldwide, including in bacteria found in healthy human and animal populations. The recent reports of colistin resistance, potentially associated with colistin usage in agriculture, further raise fears of infections that have become untreatable due to AMR. The commensal flora of humans and animals is a reservoir of AMR genes and Escherichia coli which is part of the healthy micro-flora can carry multiple AMR determinants. Antimicrobial resistance transmission within E. coli appears to be dominated by certain genetic types of the organism. However, to what extent these are restricted to certain host species (animals/humans etc.) is unknown. Such host restriction may be an important determinant of the likelihood of transmission of resistant E. coli between different reservoirs, such as between animal and human hosts. The identification of genes that allow disentanglement of the different modes of AMR transmission is crucial for a more targeted design of controls to prevent and reduce transmission of AMR. The proposed research aims to identify genes of host restriction of E. coli and their potential association with AMR transmission and occurrence. We propose to utilise whole genome sequencing of a large collection of E. coli isolates from human, animal and environmental sources in different geographic areas across Europe and in Vietnam, experimental models to study the role of host restriction determinants in transmission and bacterial fitness, and mathematical modelling. The research aims to produce a risk-assessment, estimating the contribution of different transmission routes and predicting the effect of controls on AMR. The consortium is uniquely placed to perform this research as it consists of experts in the field of microbiology and antimicrobial resistance, who work in human and animal health domains, and represent highly complementary disciplines.

The prevalence of antimicrobial resistance (AMR) is rapidly increasing worldwide, including in bacteria colonising healthy human and animal populations. The recent reports of plasmid mediated colistin resistance, potentially associated with colistin usage in agriculture, further raise fears of infections that have become untreatable due to AMR. The commensal flora of humans and animals is a reservoir of AMR encoding genes and Escherichia coli in particular can carry multiple AMR determinants. Antimicrobial resistance transmission within E. coli appears to be dominated by certain lineages. However, to what extent these are restricted to certain host species is unknown. Such host restriction may be an important determinant of the likelihood of transmission of resistant E. coli between different reservoirs, such as between animal and human hosts. The identification of determinants that allow disentanglement of the different modes of resistance transmission (i.e. bacteria vs mobile genetic elements such as plasmids) is crucial for a more targeted design of interventions to prevent and reduce transmission of resistance. The proposed research aims to identify determinants of host restriction of E. coli
and their potential association with antimicrobial resistance transmission and prevalence. We propose a One Health approach using mixed methods, including whole genome sequencing of a large collection of E. coli isolates from human, animal and environmental sources in different geographic areas across Europe and in Vietnam, experimental models to study the role of host restriction determinants in transmission and bacterial fitness, and mathematical modelling. The research aims to produce a risk-assessment, estimating the contribution of different transmission routes and predicting the effect of interventions on a single route on the overall prevalence in the different compartments. The consortium is uniquely placed to perform this research.

It is widely accepted that human and animal pathogens are a growing challenge in health systems in the UK and abroad. Unfortunately, both science and industry have fallen behind in the effort to understand and provide solutions to some of the associated issues. Therefore, our main beneficiaries at this stage will be those in the academic community however, we have described below a number of additional activities that will disseminate our findings to a wider audience and where relevant, have described the potential economic and societal impacts. The outputs of this research will have a range of applications in biotechnology and the medical, and veterinary scientific communities. The results of this work will have an impact on, public health and the development of knowledge for wealth creation.

HECTOR builds a unique One Health consortium across four European countries and introduces one Asian country. It includes academic and public health institutes each contributing essential expertise from varying contexts, thus providing all elements required to study the key research questions addressed in the JPI-AMR Transmission call. In particular, HECTOR enables analysis of an un-precedented strain collection that facilitates the study of transmission of bacterial strains and antimicrobial resistance determinants in their natural host reservoir as well as in different hosts, from healthy and disease states, from different environments and from different continents.

HECTOR enables the academic beneficiaries to expand their expertise in novel approaches towards analysis combining veterinary and human health contexts. In addition, it provides a unique opportunity to verify results of bioinformatics analyses using experimental studies in relevant hosts and to combine these data into mathematical modelling approaches that may result in opportunities for risk assessment. Ultimately, HECTOR will aid in the design of interventions that are evidence based and that target those transmission routes and modes of AMR, that are contributing substantially to transmission of AMR between humans and animals. Thus, the trans-national collaboration proposed for HECTOR will facilitate formation of a consortium that is capable of effectively addressing this due to its highly complementary constituents.

The outputs of the research proposed here will be of great benefit to policy makers such as Defra, FSA and EFSA. In addition it will be of great benefit to the scientific community. Commercial concerns will also benefit from the data generated as it may facilitate the development of novel intervention strategies.

Much of the data generated from the project will be made publicly available, further the PI and CI have strong links with other research groups, Defra, FSA, EFSA and commerce and thus will ensure information is appropriately communicated. We bring together leading experts to create and validate such models, and expect the medium to long-term impact will be felt beyond academics in the AMR field, for example by:

Industry - Defining the mechanisms of AMR transmission and persistence will facilitate the rational design of intervention strategies and products. Predictions arising from this work will be scrutinised for IP.

Policy makers - Improved strategies are required to control AMR in food-producing animals (pigs and chickens in particular). Work leading up to this proposal has already identified some of the key factors involved in AMR transmission and this data has been used as an epidemiological tool. Unravelling the factors influencing AMR transmission in E. coli will aid the effective targeting of resources and policy.

Food producers & consumers - By aiding the rational design of strategies to control AMR in food-producing animals this project will enhance animal and human health, and welfare. Therefore potential exists to improve economic & societal prosperity.