Identifying drivers of phage infectivity in natural microbial communities

Bacteria are among the most abundant organisms on earth, and are crucial for global geochemical cycling. Their viruses, bacteriophages (phages) are estimated to commonly outnumber bacteria by at least 10: 1, with phages killing around 20% of bacteria daily in the marine ecosystem. Therefore, the scale of this interaction has profound implications for global geochemical cycling.

Phages also act as vectors that spread genes between different bacteria, which can have adverse implications for human health, such as the spread of antimicrobial resistance. Phages have also acted as a source for biotechnology innovation, including commonly used enzymes for gene editing and molecular biology. Despite their importance very little is known regarding how phages shape bacterial communities in natural ecosystems.

This lack of information about these interactions is because much of our knowledge is based on the small subset of bacteria and their phages that we can grow, or 'culture', in the laboratory. Only a tiny proportion of bacteria, potentially as low as 1%, can be grown in the lab. One method that circumvents this problem is to study the DNA sequences of the microbes present, directly extracting DNA from the environment and stitching it back together using computational algorithms.

This is known as 'metagenomics' and allows us to reconstruct the profile of the microbial community, without needing to isolate or grow these microbes in the lab. However, this is a static picture of the community, and it is impossible to identify which microbes are directly interacting. A recent advance in DNA sequencing technology, called HiC sequencing, allows researchers to link DNA molecules that are present within the same cell.

This allows us to link viruses that have successfully injected their genomes into host cells, therefore capturing infections in situ.

While this new technology has exciting potential, it relies on having a complete database of viruses and hosts DNA sequences with which to link the HiC sequences. This is problematic because reconstructing all the genomes of the microrganisms present is a fundamental challenge. An analogy often used to describe this challenge is that of reconstructing an entire library of books, when all the pages have been shredded and there are different numbers of copies of each book.

In this case, each book represents a microbial genome, and the number of copies is the abundance of each organism. Another new technology, called adaptive sequencing, allows for the depletion of the common organisms, i.e. searching for rare microbes, or books in this analogy. HiC sequencing does the equivalent of providing page numbers i.e. identifying which DNA sequences are in close proximity.

Together these technologies will allow the accurate reconstruction microbial communities, and enable me to identify all viral infections in an entire community of microbes.

By combining new data from these technologies with an existing dataset of soil metagenomes, I will address fundamental questions in the ecology of phages and their hosts. Namely, who infects who? Why do some phages infect more hosts than others? Which defence mechanisms do hosts use to defend against phages? And does this interaction change across different environments, such as when bacteria are more abundant?

The research will be carried out at the University of Exeter, a leading institution for the study of microbial ecology and evolution. I will be surrounded by a collaborative group of scientists, and have access to state-of-the art sequencing technologies via the Exeter Sequencing Service, as well as high performance computing clusters. The research has implications for soil health, by understanding how phages shape the microbial community- which is crucial for plant health and development.

There is also great potential for learning more about the defence systems bacteria use against phages, many of which are of interest to biotechnology.