The devil we know? Using sequencing and metagenomics to assess the diversity of bacteria and antimicrobial resistance captured by passive surveillance
Lead Research Organisation:
University of Cambridge
Department Name: Veterinary Medicine
Abstract
Antimicrobial resistance (AMR) of bacterial infections is a serious threat to public health, and in order to halt or control its rise, understanding where it comes from and how it spreads is essential. Resistance to antimicrobial drugs in non-typhoidal Salmonella (NTS), a bacterium that infects both animals and humans, is an increasing problem, one that can lead to more severe infections and complicates treatment. A great deal of our understanding of the patterns and sources of NTS and AMR is based on data from laboratory-based surveillance and from disease outbreak investigations. These systems collect data and samples from primarily clinically ill individuals, for which there is significant under-reporting and which represent only those bacteria that cause disease. Therefore, these data characterise a relatively small proportion of the overall bacterial population. The research outlined in this fellowship proposal builds on my previous experience in epidemiology, ecology and genomics, and will address five key questions: 1) How similar are NTS and AMR from clinically diseased and non-diseased hosts? 2) For common AMR patterns found in different subtypes of NTS, are the resistance genes the same? 3) How is AMR distributed between different host populations in the same location, and how well does the observed resistance correlate with identified AMR genes? 4) How does AMR in different host populations compare between an industrialised and an industrialising country? 5) How much of the total AMR in a sample, including in bacteria that cannot be grown in standard laboratory conditions, is represented by the AMR within a single organism, NTS, which can be grown in standard laboratory conditions? I will address these questions using NTS collections from Canada and Vietnam, where in each location NTS are available from diseased and non-diseased individuals. This research will be undertaken at the University of Cambridge, in conjunction with collaborators at the Oxford University Clinical Research Unit/Wellcome Trust Major Overseas Programme in Vietnam, the University of Ottawa, Canada, and the Wellcome Trust Sanger Institute, UK.
Whole genome sequencing provides the highest resolution available to investigate how organisms are related to each other on a genetic level, and I will utilise this technology to assess how similar isolates from diseased and non-diseased hosts are to each other, the type and diversity of AMR found in each, and the degree of mixture of the populations of isolates from differing disease status hosts. I will also generate a pilot dataset applying metagenomic sequencing to faecal samples, examining all bacteria in the samples, including those can and cannot grow in standard laboratory conditions, and compare how well the AMR in the NTS isolate represents the AMR found within the total bacterial population. In addition, I will use these isolate collections to examine AMR and NTS from animal and human populations in Vietnam; given the global nature of the food supply and the wide variability of agricultural, political and sociological settings across the world, it is important to conduct such assessments in many different countries, as there is unlikely to be a single universal condition for AMR. If we are going to have the ability to do something to halt the rise in AMR, we need to know where it is, how well we are currently measuring it, and what we may be missing - the research encompassed by this proposal will provide important insight and critical data with which to address these questions.
Whole genome sequencing provides the highest resolution available to investigate how organisms are related to each other on a genetic level, and I will utilise this technology to assess how similar isolates from diseased and non-diseased hosts are to each other, the type and diversity of AMR found in each, and the degree of mixture of the populations of isolates from differing disease status hosts. I will also generate a pilot dataset applying metagenomic sequencing to faecal samples, examining all bacteria in the samples, including those can and cannot grow in standard laboratory conditions, and compare how well the AMR in the NTS isolate represents the AMR found within the total bacterial population. In addition, I will use these isolate collections to examine AMR and NTS from animal and human populations in Vietnam; given the global nature of the food supply and the wide variability of agricultural, political and sociological settings across the world, it is important to conduct such assessments in many different countries, as there is unlikely to be a single universal condition for AMR. If we are going to have the ability to do something to halt the rise in AMR, we need to know where it is, how well we are currently measuring it, and what we may be missing - the research encompassed by this proposal will provide important insight and critical data with which to address these questions.
Technical Summary
Antimicrobial resistance (AMR) of bacterial infections is a serious threat to public health; in order to halt or control its spread, understanding the drivers and reservoirs of AMR in diverse populations is essential. Non-typhoidal Salmonella (NTS), which causes tens of millions of gastroenteritis cases per year, is becoming increasingly drug resistant. Much of our knowledge of AMR and NTS is based on isolates from clinically diseased individuals, which represent only a relatively small proportion of the overall bacterial diversity. In this research, I will use whole genome sequencing and isolate collections from Vietnam and Canada to address critical gaps in our knowledge: 1) How similar are NTS and AMR from clinically diseased and asymptomatic hosts? 2) For common AMR patterns found in different serotypes of NTS, is the genetic basis the same? 3) How is AMR distributed between different contemporaneous and sympatric host populations, and how do the genetic determinants of resistance correlate to the phenotypic resistance? 4) How does AMR in different host populations compare between an industrialised and an industrialising country, where the agricultural, political and sociological conditions are different? 5) How much of the total AMR in a sample is represented by the AMR within a culturable pathogenic bacterium? If we are going to have the ability to do something to halt the rise in AMR, we need to know where it is, how well we are currently measuring it, and what we may be missing - the research encompassed by this proposal will provide important insight and critical data with which to address these questions.
Planned Impact
The research I have outlined has the potential to have both societal and economic impacts. One of the primary beneficiaries will be the communities from whom the isolates and samples were collected, particularly the individuals participating in the study in Vietnam. The results obtained from this component of my research will clarify the extent of reservoirs of antimicrobial resistance (AMR) and Salmonella in animals and humans in this setting, and may help identify transmission pathways that could then be targeted for control, or lead to changed practices such as reduced antimicrobial usage. This is particularly important given the global nature of the food supply. This information would also be relevant for health officials and government officials. I will work with the public engagement team at the Wellcome Trust Major Overseas Programme in Ho Chi Minh City to ensure that my research is disseminated in the most effective way and to the relevant stakeholders. The results relating to the Salmonella isolates from swine in Canada will be relevant to the swine industry in that country and others, as Salmonella is a targeted organism for surveillance in swine in Canada and other countries.
Another beneficiary of my research is the general public. Over the past several years, the profile of AMR has risen considerably, and individuals are increasingly aware of and have an interest in learning about the dangers and sources of AMR. What they may not be as familiar with is the under-representation of the overall bacterial populations by outbreak investigations and passive surveillance, and the impact this may on our understanding of where and how humans become infected. To facilitate the dissemination of my research to this group, I will volunteer at events like the Cambridge Science Festival, interacting with schoolchildren and the general public, and will communicate with journalists to ensure that the widest possible audience is reached.
Another beneficiary of my research is the general public. Over the past several years, the profile of AMR has risen considerably, and individuals are increasingly aware of and have an interest in learning about the dangers and sources of AMR. What they may not be as familiar with is the under-representation of the overall bacterial populations by outbreak investigations and passive surveillance, and the impact this may on our understanding of where and how humans become infected. To facilitate the dissemination of my research to this group, I will volunteer at events like the Cambridge Science Festival, interacting with schoolchildren and the general public, and will communicate with journalists to ensure that the widest possible audience is reached.
Organisations
- University of Cambridge (Lead Research Organisation)
- Government of Germany (Collaboration)
- Public Health Agency of Canada (Collaboration)
- Friedrich Loeffler Institute (Collaboration)
- Royal Veterinary College (RVC) (Collaboration)
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES) (Collaboration)
- Clermont Université (Collaboration)
- University of Guelph (Collaboration)
- Quadram Institute (Fellow)
People |
ORCID iD |
Alison Mather (Principal Investigator / Fellow) |
Publications
Baker KS
(2017)
Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: advancing global surveillance of foodborne illnesses.
in Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
Bloomfield S
(2017)
Genomic Analysis of Salmonella enterica Serovar Typhimurium DT160 Associated with a 14-Year Outbreak, New Zealand, 1998-2012
in Emerging Infectious Diseases
Bloomfield S
(2022)
Mobility of antimicrobial resistance across serovars and disease presentations in non-typhoidal Salmonella from animals and humans in Vietnam.
in Microbial genomics
Chewapreecha C
(2017)
Global and regional dissemination and evolution of Burkholderia pseudomallei.
in Nature microbiology
Chewapreecha C
(2017)
Global and regional dissemination and evolution of $\textit{Burkholderia pseudomallei}$
Chowdhury F
(2015)
Vibrio cholerae Serogroup O139: Isolation from Cholera Patients and Asymptomatic Household Family Members in Bangladesh between 2013 and 2014.
in PLoS neglected tropical diseases
Domman D
(2017)
Integrated view of Vibrio cholerae in the Americas.
in Science (New York, N.Y.)
Title | Bugs and drugs |
Description | This was a piece of artwork created by artist Tony White, as his creative reaction to the Pint of Science Festival talk given by Prof Duncan Maskell and me, "Antibiotic Resistance of the Rise", which was held at the Panton Arms in Cambridge on 18th May. |
Type Of Art | Artwork |
Year Produced | 2015 |
Impact | The artwork was on display during the Pint of Science talk we gave, and generated discussion between the audience, speakers and artist. I also brought it to the BBSRC Biennial Fellows' Conference in York, 16-17th June, as my contribution to the 'Posters and Icons' sessions. I spent the full 2 hours discussing the concept of the artwork, which is based on antimicrobial resistance (AMR), the focus of my fellowship - this led to discussions on the wider issue and how my work aims to address it. |
URL | http://www.cambridgecreativenetwork.co.uk/content/pint-science-collaboration-tony-white-and-prof-dun... |
Description | The research and effort supported by this award has led to an improved understanding of the transmission of bacteria and antimicrobial resistance (AMR) between different populations, including between different host species and in different countries. As one example, this research has revealed a novel pathway for the adaptation of Salmonella Typhimurium to invasive disease in immunocompromised patients in Vietnam. A collaborative effort produced a new tool that identifies AMR-associated genes and single base mutations from short read whole genome sequence data of bacteria. The rapid identification of AMR is important in any strategy to control AMR, and with the increased use of whole genome sequencing in clinical medicine, tools which can accurately and rapidly identify AMR directly from sequencing reads are required. The ARIBA tool is fast, accurate, and computationally efficient, offers a significant improvement on current tools, and enables a deeper understanding of the resistance associated with each bacterial isolate examined. New and expanded collaborations have also developed throughout the course of this award. This has resulted in a successful funding application for an international consortium of partners in the UK, France, Germany and Canada, and a new collaboration of partners in the UK and Vietnam. |
Exploitation Route | Research derived from this award will continue to be published in peer-reviewed journals and presented at national and international conferences. I will also continue to work with the Wellcome Trust-Major Overseas Programme in Ho Chi Minh City to ensure that the results are disseminated to those who would most benefit, including policymakers. I am also engaged with policymakers in other countries, which will ensure that the relevant research conducted in this award will be accessible to them. I will continue to interact with the general public through science festivals, schools talks and other related activities. |
Sectors | Agriculture Food and Drink Government Democracy and Justice |
Description | Whitehead Fund |
Amount | £500 (GBP) |
Organisation | University of Cambridge |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2015 |
End | 11/2015 |
Title | Additional file 1: Table S1. of Evolution of mobile genetic element composition in an epidemic methicillin-resistant Staphylococcus aureus: temporal changes correlated with frequent loss and gain events |
Description | Summary of isolates analysed in this study. (XLSX 99 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_Table_S1_of_Evolution_of_mobi... |
Title | Additional file 1: Table S1. of Evolution of mobile genetic element composition in an epidemic methicillin-resistant Staphylococcus aureus: temporal changes correlated with frequent loss and gain events |
Description | Summary of isolates analysed in this study. (XLSX 99 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_Table_S1_of_Evolution_of_mobi... |
Title | Additional file 3: Table S2. of Evolution of mobile genetic element composition in an epidemic methicillin-resistant Staphylococcus aureus: temporal changes correlated with frequent loss and gain events |
Description | Summary of MGEs identified in 923 MRSA CC22 isolates, describing distribution across the CC22 and non-CC22 isolates. (XLSX 39 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_3_Table_S2_of_Evolution_of_mobi... |
Title | Additional file 3: Table S2. of Evolution of mobile genetic element composition in an epidemic methicillin-resistant Staphylococcus aureus: temporal changes correlated with frequent loss and gain events |
Description | Summary of MGEs identified in 923 MRSA CC22 isolates, describing distribution across the CC22 and non-CC22 isolates. (XLSX 39 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_3_Table_S2_of_Evolution_of_mobi... |
Description | Bloomsbury Colleges PhD Studentship |
Organisation | Royal Veterinary College (RVC) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a PhD studentship that will commence in October 2016; I was a key contributor to the scientific content and overall study design, and wrote the initial project outline. I will act as adjunct supervisor to the student. |
Collaborator Contribution | My collaborators were key contributors to the scientific content and overall study design of the PhD studentship. They will act as official supervisors to the student. |
Impact | The outcome to date is the successful award of the PhD studentship; recruitment begins in early 2016, with a start date of October 2016. |
Start Year | 2015 |
Description | JPIAMR consortium |
Organisation | Clermont Université |
Country | France |
Sector | Academic/University |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Description | JPIAMR consortium |
Organisation | French Agency for Food, Environmental and Occupational Health & Safety (ANSES) |
Country | France |
Sector | Public |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Description | JPIAMR consortium |
Organisation | Friedrich Loeffler Institute |
Country | Germany |
Sector | Academic/University |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Description | JPIAMR consortium |
Organisation | Government of Germany |
Department | Federal Office of Consumer Protection and Food Safety |
Country | Germany |
Sector | Public |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Description | JPIAMR consortium |
Organisation | Public Health Agency of Canada |
Department | National Microbiology Laboratory (NML) |
Country | Canada |
Sector | Public |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Description | JPIAMR consortium |
Organisation | University of Guelph |
Country | Canada |
Sector | Academic/University |
PI Contribution | I am a named collaborator on a Joint Programming Initiative on Antimicrobial Resistance grant on the transmission dynamics of antimicrobial resistance. |
Collaborator Contribution | All consortium partners will carry out research to identify major transmission pathways between animals and humans and potential new intervention targets for the control of extended spectrum cephalosporin resistance. |
Impact | The project has not yet started. |
Start Year | 2017 |
Title | ARIBA |
Description | ARIBA (antimicrobial resistance identification by assembly) is a command-line tool that identifies antimicrobial resistance (AMR) determinants by a combination of mapping and local assemblies. It allows rapid AMR genotyping directly from whole genome short sequence reads, with significant improvement on previous methods. |
Type Of Technology | Software |
Year Produced | 2017 |
Open Source License? | Yes |
Impact | The manuscript was posted on bioRxiv in March 2017, and has an attention score of 112; it was published in October 2017, and has been cited 5 times so far. |
Description | Clare Hall Colloquium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I gave a lecture during a seminar series run by Clare Hall members, at the University of Cambridge. The aim of the series is to share our research with a non-specialist audience. |
Year(s) Of Engagement Activity | 2017 |
Description | Invited speaker to University of Cambridge Department of Veterinary Medicine Seminar series |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Presentation to faculty, staff and students at the Department of Veterinary Medicine at the University of Cambridge on the genomic epidemiology of bacterial antimicrobial resistance across the One Health spectrum |
Year(s) Of Engagement Activity | 2020 |
Description | Invited speaker to afternoon symposium, Department of Veterinary Medicine, University of Cambridge |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Presentation was "Mining (meta)genomics for meaningful microbial matters: pathogen and AMR transmission across the One Health spectrum" delivered at an afternoon symposium |
Year(s) Of Engagement Activity | 2020 |
Description | Invited speaker to give a seminar at the Norwegian Veterinary Institute, Oslo, Norway |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation on "Whole genome sequencing and metagenomics to understand bacterial transmission and antimicrobial resistance" on 24 February 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | Lead instructor for bioinformatics training course (Vietnam) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I was the lead instructor and organiser for a Wellcome Trust Advanced Course on "Working with Pathogen Genomes" that was hosted in Ho Chi Minh City, Vietnam, by the research unit where my collaborators work. This course helped to build bioinformatics capacity in Asia and Australasia, training researchers from these regions in tools and methods used in the analysis of whole genome sequence data from bacterial and small eukaryotic pathogens. |
Year(s) Of Engagement Activity | 2017 |
Description | London International Youth Science Forum |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I spent the day with the participants involved with this forum. I gave a lecture entitled 'Antimicrobial resistance - an international problem' to 40-50 of the participants, and then discussed key areas of debate around this issue. I then helped them develop novel and interesting ways of presenting these concepts to the rest of the 400 participants. After my talk, I was approached by a participant asking for more information on the subject area and possible hosting as a summer student. The LIYSF director wrote to say that the feedback from my lecture was very positive. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.liysf.org.uk |
Description | Pint of Science presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Discussed antimicrobial resistance (AMR) and the impact it has, and also how my research is examining this issue and how it can help address some of the problems of AMR, with members of the public. This lead to a discussion following the talk with the audience. The discussion period following the talk raised awareness in the audience about the complexity of the different drivers of antimicrobial resistance |
Year(s) Of Engagement Activity | 2015 |
URL | https://pintofscience.co.uk/event/bugs-and-drugs/ |
Description | Presentation at plasmid workshop |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Invited presentation to plasmid workshop to discuss research on AMR and plasmids |
Year(s) Of Engagement Activity | 2023 |
Description | School visit of French students (UK) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Approximately 50 French pupils attended for a school visit, and I spoke with them about pathogens and disease, and how whole genome sequencing is helping us understand both. The students were particularly interested in how it applied to understanding the spread of antimicrobial resistance. |
Year(s) Of Engagement Activity | 2016 |
Description | Seminar and instructor on training course (Vietnam) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I gave a seminar, and also acted as instructor, for a Wellcome Trust Advanced Course on "Genomics and Molecular Epidemiology of Bacterial Pathogens" that was hosted in Ho Chi Minh City, Vietnam, by the research unit where my collaborators work. This course helped to build capacity in genomics research in Asia, by training researchers from this region on pathogen genomics analytical tools and methods. |
Year(s) Of Engagement Activity | 2016 |
Description | Train the trainer: speaking to secondary school teachers about pathogen genomics |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Approximately 10 secondary school teachers attended a training event at the National Science Learning Centre in York, at which I spoke about pathogen genomics; we discussed different ways how the ideas and information could be incorporated into their schools' curricula. |
Year(s) Of Engagement Activity | 2016 |