We are seeking a highly motivated PhD student to join a multidisciplinary project aimed at identifying bacteriophage-associated factors that contribute to bacterial fitness, virulence, and evolution in the globally important species Enterococcus faecalis and Enterococcus faecium.

1. faecalis and E. faecium, commonly found as part of the healthy gut flora in humans and animals, have become significant opportunistic pathogens in recent years. These bacteria are responsible for a variety of infections, including endocarditis and urinary tract, wound, and bloodstream infections, and are commonly associated with the hospital environment. Owing to increasing rates of resistance to last-resort antibiotics, phage therapy — using bacteriophages to treat bacterial infections — has been suggested as a potential solution for multidrug-resistant enterococcal infections¹. However, detailed understanding of the fundamental roles that bacteriophages play in enterococcal biology is currently lacking.

Bacteriophages (‘phages’) play important roles in bacterial ecology and evolution^2-4. Temperate phages, the most prevalent type of phages within the human microbiome, can reversibly integrate into their bacterial host’s chromosome to form a prophage. Prophages can exert a myriad of effects upon their host bacteria, ranging from contributing critical virulence factors that are key to clinical disease (e.g. toxins), through to providing the bacterium with immunity against further phage infection: a feature that carries significant implications for the success or failure of phage therapy approaches. Furthermore, induction of prophages into the lytic cycle can result in highly efficient horizontal gene transfer between bacteria, potentially driving the rapid emergence of pathogenic or phage-resistant strains^4-5. Though enterococci are ranked as priority pathogens by the World Health Organisation and phage therapy is actively being considered for these increasingly hard-to-treat infections, our knowledge about the roles that prophages play in i) the ability of their host bacteria to cause infections, ii) their ability to interfere with phage therapy interventions, and iii) what unintended side effects phage therapy might induce, is very limited.

Supervised by Drs Suzie Humphrey and Eva Heinz, this PhD project will employ an integrated computational and experimental approach to conduct genomic and functional characterization of prophages in enterococcal strains isolated from various clinical sources. The successful candidate will receive training in a diverse range of techniques, including sequence analyses, comparative genomics and protein family evolution; microbiology; biochemistry and molecular biology, including the use of CRISPR-based systems for targeted mutagenesis. The outcomes of this research will enhance our fundamental understanding of enterococcal biology and will provide valuable insights that could lead to novel therapeutic strategies for treating enterococcal infections.

References:

1 Stellfox ME, Fernandes C, Shields RK, Haidar G, Hughes Kramer K, Dembinski E, Mangalea MR, Arya G, Canfield GS, Duerkop BA, Van Tyne D.  Bacteriophage and antibiotic combination therapy for recurrent Enterococcus faecium bacteremia. mBio 15:e03396-23 (2021). https://doi.org/10.1128/mbio.03396-23

2 Humphrey, S., Fillol-Salom, A., Quiles-Puchalt, N. et al. Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements. Nat Commun 12, 6509 (2021). https://doi.org/10.1038/s41467-021-26004-5

3 Humphrey, S., San Millán, Á., Toll-Riera, M. et al. Staphylococcal phages and pathogenicity islands drive plasmid evolution. Nat Commun 12, 5845 (2021). https://doi.org/10.1038/s41467-021-26101-5

4 Fillol-Salom, A., Bacigalupe, R., Humphrey, S. et al. Lateral transduction is inherent to the life cycle of the archetypical Salmonella phage P22. Nat Commun 12, 6510 (2021). https://doi.org/10.1038/s41467-021-26520-4

5 Alfred Fillol-Salom, Jakob T. Rostøl, Adaeze D. Ojiogu, John Chen, Gill Douce, Suzanne Humphrey, José R. Penadés, Bacteriophages benefit from mobilizing pathogenicity islands encoding immune systems against competitors, Cell, 185, 3248-3262.e20 (2022). https://doi.org/10.1016/j.cell.2022.07.014