Probing the evolution of the protein translocation process using the novel bacterial exotoxin, mycolactone

Second supervisors: Peter Mayerhofer and/or Emma Laing

We are seeking to recruit an enthusiastic and committed PhD student to investigate the evolution of the Sec61 translocon and the ability of a novel bacterial exotoxin inhibitor to act on translocons from different genera.

Background: Buruli ulcer is a rare but devastating “flesh-eating” skin infection caused by Mycobacterium ulcerans. These bacteria produce a unique cytotoxic polyketide called mycolactone which drives disease pathology. We recently identified the molecular target of mycolactone, showing it to be a powerful inhibitor of the mammalian Sec61 translocon. This cellular machine plays an essential role in protein export, by moving proteins between the cytoplasm and endoplasmic reticulum.

It is an exciting time to be working in Dr Simmonds’ lab. Our discovery has opened up great possibilities for improving our understanding of both Buruli ulcer pathogenesis and the fundamental cellular process of protein translocation. In particular, the mode of transmission of the disease is still unknown. The bacteria is considered to be an opportunistic environmental pathogen but little is known of its niche and whether or not there exist any natural hosts and vectors that might promote human infection. The vital unanswered question you will help answer in this project is: why does the bacteria expend such vast energy making mycolactone?

The project: You will answer this question by investigating the ability of mycolactone to inhibit protein translocation in different genera that M. ulcerans would encounter in its natural habitat; including bacteria, algae, insects, arthropods, fish, plants etc. Combined with bioinformatic analysis and empirical determination of the genes homologous to mammalian Sec61 you will uncover which species are sensitive to mycolactone’s effects and what factors determine that sensitivity. To achieve this you will receive training in a wide range of world-class molecular and cell biology research techniques. There are opportunities for field work in Africa to collect samples for analysis.
This is a fantastic opportunity to join a thriving research team that is funded by a Wellcome Trust Investigator Award to Dr Simmonds that seeks to understand Buruli ulcer pathogenesis. The WHO has defined Buruli ulcer as a Neglected Tropical Disease and, in addition, your research will also impact our understanding of other conditions such as cancer and autoimmunity because protein translocation is vital in many normal and pathological disease states.

The ideal candidate for this post would have a passionate interest in molecular/cell biology, be an aspiring ‘molecular detective’ and have a strong sense of curiosity.

Applicants should have:

1. A good undergraduate or master’s degree in molecular biology, cell biology, biomedical science or a closely allied discipline
2. Demonstrated aptitude for research
3. Motivation and enthusiasm for molecular biology, and be capable of thinking and working independently.
4. British residency or EU nationality. Funding for overseas students is limited and overseas students are encouraged to find suitable funding themselves.

The university values diversity and is committed to equality of opportunity.

Contacts and how to apply:

Candidates should contact Dr Simmonds ([Email Address Removed], 01483 684714) in the first instance for an informal chat.

Applications should be submitted online through the link available on the Microbial Sciences PhD web page (https://www.surrey.ac.uk/postgraduate/microbial-and-cellular-sciences-phd). During the application process you will be asked to submit relevant documents including a CV, covering letter, and transcript of your degree. In the ‘Research Proposal’ section of the application please enter the project title given above, provide a very brief personal statement that highlights your research experience/interests to date, and identify that you wish to work with Dr Simmonds.

Keywords: Sec61, evolution, molecular biology, genetics, protein biochemistry, translocation, cancer, cell biology