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Structure-function studies of Legionella pneumophila type-II secretion system substrates and the molecular basis of their recognition during export

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  • Full or part time
    Dr Garnett
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Applications are invited for a PhD studentship in Dr. James Garnett’s group at Queen Mary University of London.

Background: the research activity of the group is focused on understanding the key virulence traits of bacteria that allow them to establish infection and persist within the host and the environment. Legionella pneumophila is an opportunistic Gram-negative bacterium, ubiquitous in natural and anthropogenic freshwater environments. It is the causative agent of Legionnaires’ disease, an often-fatal pneumonia, and Pontiac fever, a milder flulike disease. Man-made infrastructures that store and distribute water are omnipresent in Western society and these bacteria can be found in many large buildings, including hospitals and hotels. The high prevalence of Legionella within the environment is due to its ability to survive within biofilms or as an intracellular parasite of biofilm associated protozoa. L. pneumophila uses a type II secretion system (T2SS) to translocate substrates across its outer membrane, where they support biofilm formation, replication in the host, dampening of cytokine output and survival in mammalian lungs. A number of these substrates have unique amino acid sequences only found in Legionella spp. and furthermore they have been implicated in promoting broad host tropism and persistence of disease. Translocation involves a number of recognition events but intriguingly these substrates are identified via common ’conformational’ motifs on their natively folded surfaces. The T2SS is also a major virulence factor in other human pathogens (e.g. Chlamydia trachomatis, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp., Yersinia enterocolitica) and understanding its mechanism of secretion may provide the bedrock for targeted development of sustainable prevention and control strategies for a range of infectious diseases. Our group takes a multidisciplinary approach in our research using a range of complementary structural biology procedures (X-ray crystallography, solution state NMR and SAXS) coupled with cellular, biochemical and other biophysical techniques. We also have strong links with the National Institute for Medical Research, Diamond Light Source and Imperial College London. This provides an excellent training environment and the intellectual framework for a talented, postgraduate student to deliver a deeper understanding of the L. pneumophila T2SS and its substrates.

Aims:
(i) To determine the molecular details of type-II dependent substrate recognition in L. pneumophila.
(ii) To determine the structure-function relationship of unique L. pneumophila substrates involved in disease or ecology.

Techniques and Training: the successful candidate will be trained in a wide range of biochemical and biophysical techniques to study L. pneumophila T2SS proteins, including cloning, large-scale protein purification, X-ray crystallography, solution state NMR, SAXS, ITC, Biacore, DSF etc. Moreover, there will also be the opportunity to perform in vitro functional and also in vivo cell interaction assays, and the student will gain experience in Unix-based operating systems. The training will also include the development of skills essential for career progression, including management of research projects, presentation and writing skills.

Environment: Queen Mary University of London is a member of the Russell group and is one of the leading research-focused institutions in the UK. All PhD students and post-doctoral researchers are part of the QMUL Doctoral College, which provides support with high-quality training and career development activities.

Application: for informal enquires please contact Dr. Garnett and include your CV, a covering letter explaining eligibility and interest in the project and the contact details of two academic referees.

Funding Notes

Applicants wishing to apply for PhD funding through Ciência sem Fronteiras, CONACYT or the China Scholarship Council are welcomed, as are those applicants who can self-fund.
Applicants should be able to demonstrate that they can cover the cost of living expenses and tuition fees for a minimum of 3.5 years. However, the School does offer a limited number of tuition fee only scholarships for excellent applicants and if you wish to apply for these you should discuss this with your potential supervisor.

References

Garnett, JA, Muhl, M, Douse, C, Busch, B, et al: Structure-function analysis reveals that the Pseudomonas aeruginosa Tps4 two-partner secretion system is involved in CupB5 translocation. Prot. Sci. (2015) early view.
Young, JC, Clements, A, Lang, AE, Garnett, JA, et al: The Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation. Nature Commun. 5 (2014) 5887.
Garnett, JA, Martínez-Santos, VI, Saldaña, Z, Pape, T, et al: Structural insights into the biogenesis and biofilm formation by the E. coli common pilus. Proc. Natl. Acad. Sci. U.S.A. 109 (2012) 3950-3955.
Garnett, JA & Matthews, S: Interactions in bacterial biofilm development: a structural perspective. Curr. Prot. Pept. Sci. 13 (2012) 739-755.
Korotkov, KV, Sandkvist, M. & Hol, WG: The type II secretion system: biogenesis, molecular architecture and mechanism. Nature Rev. Microbiol. 10 (2012) 336-51.
Cianciotto, NP: Many substrates and functions of type II secretion: lessons learned from Legionella pneumophila. Future Microbiol. 4 (2009) 797–805.

How good is research at Queen Mary University of London in Chemistry?

FTE Category A staff submitted: 14.00

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