Real-time host-parasite coevolution in natural microbial communities

The functioning of all ecosystems is ultimately dependent on the diversity of its community of bacteria. A key factor maintaining diversity in these communities are viruses that reproduce inside and ultimately kill bacteria. Our recent work has shown that bacteria and their viruses are literally evolving in the soil all around us over a matter of days, locked into coevolutionary arms races where bacteria evolve resistance to viruses and viruses evolve to overcome this defense. As well as affecting community structure, this rapid coevolution has other important indirect effects, such as causing the evolution of 'mutator' bacteria that pose a significant health risk to other organisms. Our aim is to follow and characterise these real-time coevolutionary arms races between bacteria and viruses in natural environments: something never previosuly done for any organisms. By using unique genetic markers, we can release and then re-capture through time the evolving bacteria and viruses. We will take advantage of our experience using next generation sequencing to link changes in resistance and infectivity traits with mutations occurring within the genomes of the organisms.
In addition to characterising these coevolutionary dynamics, we will test hypotheses about how the environment affects coevolution. Our preliminary work suggests that coevolution is likely to fundmantally differ based on the extent to which soil is mixed, and how close bacteria are to plants, which exude highly nutritious food for bacteria. Specifically, the arms race will be more intense and hence be of greater significance for structuring communities in well mixed soil around plants.
While the work investigates natural bacteria-virus coevolutionary interactions in soil, the broader implications are extensive. First, there is increasing interest in using viruses to kill bacteria that cause infections of humans, animals and crops, hence determing the significance of evolution in the fight between these organisms is crucial. Second, the study of real-time coevolution in natural environments has simply not been possible in any other system, allowing us to test fundamental hypotheses developed through decades of theoretical work, natural surveys and laboratory studies.

The proposed work will provide an unambigous demonstration of real-time coevolution between bacteria and viruses (along with the archea, the most common groups of organisms on the planet) within a natural community. Moreover, it will allow us to identify the key environmental drivers of coevolution in soil, and some of the consequences for molecular evolution. This will be the first example of real-time genetic and phenotypic coevolution in a natural environment for any organisms, hence the work will primarily be of academic benefit. We have identified three additional beneficiaries: 1) charities and industry involved in phage therapy; 2) the food industry; 3) the general public. The benefits to these groups, and how we will implement the benefits, are outlined below.

1. Charities and Industry involved in phage therapy.
In light of the high frequency of antibiotic resistant bacteria, there is a resurgence of interest in the use of phages as therapeutic and prophylactic antimicrobials in clinical and agricultural contexts. Understanding coevolutionary dynamics between bacteria and phages has crucial implications for the evolution of resistance to phage therapies. I am a member of a charitable organisation (Phages For Human Application Group Europe) promoting research into phage therapy, and we will ensure results are disseminated through this organisation.
Buckling was recently a member of delegation to the European Medicines Agency, a body whose role it is scientifically evaluate new medicines, to obtain support for phage therapy. The Agency was very receptive to our requests, but emphasised the need for more data in natural contexts and modelling of coevolutionary interactions. We will inform the EMA via a new delegation of our results, bringing clinical phage therapy a step closer to reality in the EU.
We have also been in contact with a phage therapy biotech company whose current approach is the use of a standardised phage cocktail. By showing them the rate and significance of coevolution in these natural settings, coevolution will hopefully become a consideration in their development of therapeutics.

2. Food industry.
While phages have the potential to be important antimicrobials in medicine and agriculture, phages themselves can be a major problem in the food industry. Millions of pounds are lost every year as a result of phage contamination of foods that require bacterial fermentation, such as cheese and sauerkraut. We will contact some of the larger UK cheese producers (notably Dairycrest) to inform them of our research, and potentially develop collaborations to study interactions between cheese bacteria (e.g. Lactobacilli) and phages. We have already made contact with researchers at Wageningen University, the Netherlands, who work closely with the cheese industry, and they were very receptive about collaborations.

3. Public understanding of Science.
While there is awareness of microevolution, most obviously in the context of human disease (e.g. antibiotic resistance, influenza immune escape, etc), there are few popular and general examples. The concept of bacteria and phage locked in an evolutionary arms race all around us will hopefully emphasise evolution as a force that affects everyone's life. As we have done on a number of past occasions, we will promote the work through the popular science magazines and the normal media. In order to maximise the impact, we will work with a dedicated Research Development Manager (RDM) based in the Research and Knowledge Transfer Office. The project team will also organise a series of public lectures in schools and colleges in Cornwall, as they have successfully done for other members of the Centre for Ecology and Conservation.