Investigation of a novel DNA modification pathway that promotes bacterial immunity

Bacteriophages (phages) are viruses that can specifically infect bacteria. They co-exist in every niche, where phages outnumber bacteria by an estimated 10-fold. The resulting selective pressure has led bacteria to evolve a plethora of defence strategies, with phages co-evolving counter-resistance mechanisms to evade bacterial immunity.

In the last few years, the increasing effort to understand bacterial immunity against phages has unveiled the existence of many defence systems. Several novel defence systems discovered in the last few years were characterised, and their mechanism involves novel nucleotide modifications, signalling, and cell death strategies. Furthermore, these recent discoveries provided the unprecedented revelation of an evolutionary link between some antiphage systems and the innate immunity components of humans and plants. 

Nevertheless, the full diversity of anti-phage systems and details of their molecular mechanism remain to be determined. This research will aim to close this fundamental gap in understanding the diversity of defence systems encoded in bacteria and deciphering their mode of action. 

In preliminary work, we have identified a novel candidate system in Serratia marcescens. The PhD student will use a combination of state-of-the-art approaches, including molecular microbiology, fluorescence microscopy, structural biology, biochemistry, mass-spectrometry and comparative genomics to characterise one of the novel defence systems we have discovered. 

Our preliminary work shows that the novel system provides strong defence against phages by introducing a novel nucleic acid modification. 

This research will aim to identify the type of nucleic modification used by each subtype to prevent phage propagation, including determination of the structure of the defence proteins with their substrate. Furthermore, we will decipher the timeframe of recruitment of the defence system, following phage infection, and which stage of the phage infection cycle is compromised by this novel nucleic acid modification. Furthermore, we will investigate the counter-defence strategies that phages can against the novel defence system.

Supervisors

• Giusy Mariano
• Graham Stewart

Applicants for this studentship will have an enthusiastic and strong interest in microbial genetics, molecular biology or comparative genomics.

Prior knowledge of python and bash language are desirable but not necessary.

Candidates will need to meet the minimum entry requirements for our PhD programme. Open to UK or international candidates.