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MRC DiMeN Doctoral Training Partnership: How do superbugs hide from the host? Understanding the mechanisms of innate immune evasion in the opportunistic pathogen Enterococcus faecalis

  • Full or part time
  • Application Deadline
    Monday, January 21, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

All enterococci produce a surface polysaccharide called the enterococcal polysaccharide antigen (EPA) that plays a key role during pathogenesis (Mistou et al., 2016). EPA is is encoded by two gene clusters: (i) 18 genes extremely conserved, encoding a core synthetic machinery and (ii) 10-20 genes variable from one strain to another, responsible for the decoration of the polysaccharide backbone. Our results indicate that mutants in the decoration genes display morphological defects, an altered susceptibility to beta-lactams and are no longer virulent in a zebrafish model of infection (Prasjnar et al., 2013; Smith et al., 2018). We hypothesize that EPA plays a major role for the cell surface display of proteins involved in cell wall synthesis and that the decoration of this polymer mediates innate immune evasion during pathogenesis.

The aim of this project is to investigate how EPA contributes to E. faecalis antimicrobial resistance and virulence. Three objectives will be set.
1. Explore the role of EPA in cell growth and resistance to antimicrobials. We will use available E. faecalis recombinant strains which no longer or conditionally produce EPA to investigate the contribution of this polymer to cell wall structure and dynamics. We will also explore how EPA modulates the capacity of antimicrobials targeting the cell envelope (eg., beta-lactams, cationic peptides, bile salts) to bind and penetrate the cell walls.

2. Investigate the role of EPA during pathogenesis. We will study (i) how EPA and its decoration modulate recognition by macrophages and neutrophils during pathogenesis, using both in vitro phagocytosis assays and the zebrafish model of infection and (ii) investigate the role of EPA on bacterial population dynamics in the host. We will test if soluble EPA can be used as a decoy molecule to evade phagocytosis.
3. Explore the cell signalling pathway triggered by enterococci during infection. We will use in vitro phagocytosis assay in primary human and murine macrophages to identify signal transduction cascades that shape the host response to enterococcal infections.

This project will involve a multidisciplinary approach underpinned by the complementary expertise of 3 supervisors: Dr Stephane Mesnage (https://www.sheffield.ac.uk/mbb/staff/stephanemesnage), Dr Phil Elks (https://elkslab.weebly.com/) and Pr Endre Kiss-Toth (https://www.sheffield.ac.uk/iicd/profiles/kiss-toth). The experimental approach will involve biochemistry (cell wall structural analysis), molecular genetics (construction of mutants), cell biology (in vitro phagocytosis assays and innate immune signalling), and cutting edge imaging (to study bacterial cell surface organisation and host-pathogen interactions).

The project will be set in the context of the Florey institute (http://www.floreyinstitute.com), a university initiative that brings together researchers from the basic science to clinical application to address the challenge of antimicrobial resistance and host-pathogen interaction.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

Relevant publications

Mistou, M. Y., Sutcliffe, I. C., and van Sorge, N. M. (2016) Bacterial glycobiology: rhamnose-containing cell wall polysaccharides in Gram-positive bacteria. FEMS Microbiol Rev 40, 464-479

Prajsnar TK, Renshaw SA, Ogryzko NV, Foster SJ, Serror P, Mesnage S. (2013) Zebrafish as a novel vertebrate model to dissect enterococcal pathogenesis. Infect Immun. 81, 4271-9.

Smith RE, Salamaga B, Szkuta P, Hajdamowicz NH, Prajsnar TK, Bulmer G, Fontaine T, Kołodziejczyk J, Herry JM, Hounslow A, Williamson MP, Serror P, Mesnage S. (2018) Decoration of the enterococcal polysaccharide antigen EPA is essential for virulence, cell surface charge and sensitivity to effector molecules of innate immunity. Biorxiv doi: https://doi.org/10.1101/479022

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