Multi-layered bacterial genome defences: linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities.
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Biosciences
Abstract
The spread of antimicrobial resistance (AMR) is a slow-moving pandemic that has been identified by the WHO as one of the top 10 threats facing humanity. Plasmids and other MGEs play a key role in the dissemination of AMR, but we have only a rudimentary understanding of the factors that determine if and how MGEs spread through microbial communities. It is generally assumed that bacterial immune systems are a major determinant, but existing studies are limited to only a few stand-alone defence systems. The development of novel bioinformatics approaches led to the discovery of dozens of formerly unknown defences, often clustered within genomic loci known as 'defence islands'. This suggests that bacterial genome defences consist of multiple integrated layers that act in concert to constrain MGE infections; analogous to how our own innate and adaptive immune systems work together to combat pathogen infections. While our preliminary data supports this hypothesis, systematic studies that rigorously examine this novel conceptual framework are lacking.
Recent studies by our team members have shown that co-occurring defences can interact synergistically to provide high levels of multi-layered defence. This is extremely novel and raises many important questions. For example, how common is it for different combinations of defences to co-occur in a bacterial genome? What causes defences to interact synergistically or antagonistically? How is expression and activity of multi-layered defences orchestrated within a bacterial cell? And how do bacteria balance the need for strong multi-layered defence against the need to take up beneficial genes?
We assembled a multi-disciplinary team of world-leading UK researchers to tackle some of the most pressing questions in the field of microbial genome evolution. Our ambitious goal to tease apart how complete, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities requires complementary expertise and experimental capacity in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy, and experimental evolution techniques. Our research program provides a new tier in our understanding of bacterial genome evolution and goes well beyond the frontiers of bioscience knowledge. The multidisciplinary approaches that are pioneered will transform our understanding of the role of bacterial immune systems in microbial genome evolution and will boost international competitiveness of UK Bioscience. This research falls in the BBSRC priority areas of integrative microbiome research, combatting AMR, systems approaches to biosciences and data driven biology. As far as we know no other team is engaged in addressing these important questions at a scale that is proposed here.
Recent studies by our team members have shown that co-occurring defences can interact synergistically to provide high levels of multi-layered defence. This is extremely novel and raises many important questions. For example, how common is it for different combinations of defences to co-occur in a bacterial genome? What causes defences to interact synergistically or antagonistically? How is expression and activity of multi-layered defences orchestrated within a bacterial cell? And how do bacteria balance the need for strong multi-layered defence against the need to take up beneficial genes?
We assembled a multi-disciplinary team of world-leading UK researchers to tackle some of the most pressing questions in the field of microbial genome evolution. Our ambitious goal to tease apart how complete, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities requires complementary expertise and experimental capacity in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy, and experimental evolution techniques. Our research program provides a new tier in our understanding of bacterial genome evolution and goes well beyond the frontiers of bioscience knowledge. The multidisciplinary approaches that are pioneered will transform our understanding of the role of bacterial immune systems in microbial genome evolution and will boost international competitiveness of UK Bioscience. This research falls in the BBSRC priority areas of integrative microbiome research, combatting AMR, systems approaches to biosciences and data driven biology. As far as we know no other team is engaged in addressing these important questions at a scale that is proposed here.
Technical Summary
Bacteria have evolved sophisticated defences against infections by mobile genetic elements (MGEs), including phages and plasmids, that shape genome structure and function. The recent discovery of dozens of diverse and formerly unknown defence systems that cluster in 'defence islands' has led to the hypothesis that their immune systems consist of multiple integrated layers that act in concert to constrain MGE infections. We will combine genomics, modelling and experimental analyses to holistically examine how multiple defence systems in the same cell interact to block MGE infections, and how this shapes the spread and evolution of MGEs in bacterial communities. We will carry out large-scale bioinformatics analyses to map the distribution and co-occurrence patterns of bacterial defences and MGEs. This will be complemented with high-throughput infection assays with hundreds of bacterial isolates to identify which defences interact synergistically. We will combine bioinformatics and transcriptomics analyses to identify general concepts in the regulation of multi-layered defences, which will be complemented with biochemical and structural analyses to identify mechanisms of targeting, small-molecule activation and their molecular interactions. Finally, we will apply experimental evolution approaches to understand when, where and why multi-layered defences are favoured by selection, and the costs they carry for the host. In our selection experiments, we will gradually build complexity: from simple clonal populations to microbial communities and from static to mobile defence islands. This study will propel our understanding of microbial genome evolution while generating knowledge of applied importance for the prediction and prevention of antimicrobial resistance. Findings from P. aeruginosa will be generalised using bioinformatics, modelling and a limited number of carefully selected infection experiments with other bacterial species to identify general rules of life.
Organisations
- UNIVERSITY OF EXETER (Lead Research Organisation)
- University of Manchester (Collaboration)
- DURHAM UNIVERSITY (Collaboration)
- University of Bath (Collaboration)
- University of St Andrews (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- University of Bristol (Collaboration)
- University Medical Center Utrecht (Project Partner)
Publications
Agapov A
(2024)
Multi-layered genome defences in bacteria.
in Current opinion in microbiology
Alseth EO
(2024)
The impact of phage and phage resistance on microbial community dynamics.
in PLoS biology
Description | sLoLa consortium |
Organisation | Durham University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of Bath |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of Cambridge |
Department | Cambridge Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of Liverpool |
Department | Liverpool Sequencing facility |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of Manchester |
Department | Manchester Museum |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |
Description | sLoLa consortium |
Organisation | University of St Andrews |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | lead PI of the consortium |
Collaborator Contribution | The BBSRC sLoLa Multi-layered bacterial genome defences (MultiDefence) project is focused on linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities. It investigates the defence mechanisms of bacterial cells, to help stop the spread of drug-resistant genes. The project team includes researchers from the universities of Exeter, Cambridge, Durham, Manchester, Bath, Bristol, Liverpool and St Andrews. Our ambitious goal is to tease apart how complex, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities. This requires expertise in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy and experimental evolution techniques - so we have assembled a team of world-leading UK researchers covering all these fields. The aim is to uncover defence systems that could be exploited for engineering biology, especially using phages (viruses that infect bacteria). Unpicking the complex interactions among mobile genetic elements, phages, and bacterial defence systems in natural populations is key to understanding antimicrobial resistance dynamics. Our research programme builds on the very recent discovery of a large diversity of defence systems that frequently co-exist in the same cell, where they cluster in 'defence islands'. True to our aim of building a vibrant community in the field of microbial genome defence biology in the UK, the network has been operating in an inclusive manner. We have been delighted to include ECRs funded through other means from our participating principal investigators (PI) and their labs. This has resulted in a very productive community where we can stimulate collaboration, maximize the benefits of the consortium and broaden the depth of expertise and research cultures of the team(s). |
Impact | Multi-layered genome defences in bacteria. Agapov A, Baker KS, Bedekar P, Bhatia RP, Blower TR, Brockhurst MA, Brown C, Chong CE, Fothergill JL, Graham S, Hall JP, Maestri A, McQuarrie S, Olina A, Pagliara S, Recker M, Richmond A, Shaw SJ, Szczelkun MD, Taylor TB, van Houte S, Went SC, Westra ER, White MF, Wright R. Curr Opin Microbiol. 2024 Feb 17;78:102436. doi: 10.1016/j.mib.2024.102436. Online ahead of print. PMID: 38368839 Review. |
Start Year | 2023 |