Van Houte Lab
Van Houte Lab
Welcome to our website! The van Houte lab is based in the Environment and Sustainability Institute at the University of Exeter’s Cornwall Campus. The van Houte lab works closely together with the Westra lab and shares lab space and facilities in the ESI with the Westra lab, the School of Mines, and the European Centre for Environment and Human Health.
We study interactions between mobile genetic elements (MGEs, including bacteriophages and plasmids) and their bacterial hosts. We often use a combination of molecular genetics, bioinformatics and experimental evolution approaches, and always strive to use ecologically relevant model systems. While most of our research is fundamental in nature, we aim to apply this fundamental knowledge to tackle real-world challenges, for example around the spread of antimicrobial resistance (AMR), the potential for microbiome engineering and the development of phage therapy as an alternative to antibiotics.
Our current research themes include:
The spread of AMR is a slow-moving pandemic, identified by the WHO as a top 10 threat facing humanity. MGEs play a key role in AMR dissemination, but also present a promising basis for non-antibiotic therapies. Theory and experiments have greatly advanced our understanding of how MGEs and the genes they carry spread through bacterial populations.
Funded by the ERC Starter grant MUSIC (which, due to non-association of the UK to the Horizon 2020 programme, is now funded through the UKRI guarantee fund instead), we aim to understand how the spread, activity and evolution of MGEs in microbial communities is shaped by bacterial defences. In a microbial community context, where multiple different bacterial strains or species co-exist and potentially interact, the flux of MGEs between constituent species and strains will have a profound impact on the bacteria- MGE associations that establish. We combine experimental and bioinformatics approaches to examine the relative importance of different bacterial defences in determining MGE transmission between species and across communities. We focus on several of the ESKAPEE (E. coli, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecium, Enterobacter spp.) pathogens, which cause hard to treat infections due to their rapid acquisition of AMR genes that are vectored by different types of MGEs. In collaboration with colleagues from the University of Liverpool and UMC Utrecht, we now have a collection of >2000 clinical isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae and pathogenic E. coli isolates, which we analyse bioinformatically in collaboration with the Baker lab (University of Cambridge). We have also recently set up high-throughput assays to directly measure the contribution of host defence genes in driving variation in MGE infection success and maintenance, a.o. using flow cytometry and cell sorting experiments.
In addition, over the past few years we have also studied the epidemiology of anti-CRISPR-phages. Funded by a BBSRC New Investigator Award (2020-2024) we study how anti-CRISPR phages work together to overcome CRISPR-Cas immunity. For this we use a combination of bulk experiments and single-cell microscopy. For the latter we use microfluidics devices in collaboration with the Pagliara lab .
Lab members on this project include Rama Bhatia, Anna Olina and Benoit Pons.
Successful development of phage therapy applications requires a deep understanding of the factors that determine phage infectivity and host resistance, and how these traits evolve over time. Well-known bacterial defences include Restriction-Modification (RM) and CRISPR-Cas, which revolutionised our ability to manipulate DNA in vitro and in vivo. Bacteria can also mutate cell surface receptors or trigger dormancy/cell death upon infection (known as Abi) to prevent phage replication. The last decade has seen an astonishing number of new bacterial defences being discovered. For the majority of those, we don’t know the relative importance of those systems for the bacteria that carry them. Different defences act at different stages of the phage lifecycle: some cleave phage genomes immediately following infection, others interfere with phage transcription or replication, or induce cell death or dormancy responses. Since diverse defence systems frequently coexist in the same genome, it has been hypothesised that bacterial defence systems consist of multiple integrated layers that act in concert to constrain phage infections, by providing broader spectrum or higher levels of defence than single systems. Analogous to our own innate and adaptive immune systems, activation of multi-layered defences in bacteria needs to be well orchestrated. As part of the UK consortium MultiDefence, which is funded by a BBSRC sLoLa grant, we aim to understand if and how co-occurring defences integrate, and how multi-layered defences shape bacteria-MGE interactions, necessary to control and outflank AMR. We focus here on the opportunistic pathogen Pseudomonas aeruginosa, which is a WHO priority pathogen due to its ability to rapidly evolve drug resistance and its ubiquitous nature. More information on this project can be found here.
As part of this project, and in collaboration with the Fothergill lab (Univ of Liverpool) and the Brockhurst lab (Univ of Manchester) our lab has recently set up large-scale infection assays using a collection of P. aeruginosa isolates and >100 phages to map infectivity and resistance patterns. The next step will be to link those to bacterial genotypes using GWAS and machine learning approaches. We apply classical forward and reverse genetics approaches to demonstrate causal genotype- phenotype relationships, to identify which defences interact synergistically, the range of resistance they confer, and use experimental evolution to understand how robust they are against phage evolution. The ultimate aim of this research is to predict infectivity patterns of phage from genetics data in order to develop and optimize personalized phage therapy in the clinic.
Lab members on this project include Anna Richmond, Aleksei Agapov, and Alice Maestri.
Decades of consistent overuse of antibiotics have selected for high levels of antimicrobial resistance (AMR) in bacteria. Consequently, AMR presents one of the most pressing problems of our time, and finding novel ways to eradicate AMR is of major medical importance. A highly promising strategy to combat AMR is to remove AMR genes using CRISPR-Cas9, a reprogrammable sequence-specific nuclease that is part of a bacterial immune system. However, CRISPR-Cas9 delivery to target bacteria is still a major challenge that must be overcome before this approach can be used in the clinic. Our team has developed an approach that uses a conjugative plasmid with an exceptionally wide host range to deliver CRISPR-Cas9 to remove AMR genes from bacterial species that are part of a microbial community. Funded by a Lister prize from the Lister Institute for Preventative Medicine, we currently focus on AMR removal in E. coli sequence type (ST) 131, which is a common cause of bloodstream infections worldwide. In addition, we are part of the MISTAR consortium, funded by the JPI-AMR programme, in which we currently focus on highly drug-resistant clinical isolates of the pathogen Klebsiella pneumoniae.
Lab members on this project include David Sünderhauf and Clàudia Morros.
Rising levels of antimicrobial resistance threaten healthcare systems worldwide and the global economy. Phage therapy (PT) has proven to be an effective last-resort treatment against multidrug resistant bacterial infections, but faces multiple barriers to its widespread use. The use of synthetic phages could overcome many of these barriers, particularly with respect to protection of intellectual property enabling commercialization. However, despite the potential scientific and commercial advantages, synthetic PT faces major challenges surrounding release of synthetic viral organisms to ensure the responsible use of these synthetic biology innovations and prevent their misuse.
Lead by our collaborator Mike Brockhurst (University of Manchester), we obtained funding from the BBSRC as part of the Engineering Biology Mission Awards call. In this SafePhage Mission Award, we focus on the development of genome safeguarding technologies for synthetic phages that will ensure their long-term biosecurity and biocontainment. Such safety mechanisms are inherent to all mature technologies and, here, must be robust to the evolution of escape mutants whilst not negatively impacting treatment efficacy. Here in Penryn, a team consisting of postdoc David Sünderhauf and technician Abdul Basit focus on the design and production of high-efficiency production hosts for rebooting synthetic phages.
Stineke van Houte, Principal Investigator: C.van-Houte@exeter.ac.uk
Hannah Westlake, Project Admin: H.E.Westlake@exeter.ac.uk
