Posted on 16 March 2017
Membrane effects of bacterial lipoteichoic acid (LTA) on chemokine receptors.
Applications are invited for a 3-year PhD in Medical Sciences studentship funded by the Hull York Medical School at the University of York. This project aims to establish the molecular basis of S. aureus LTA-mediated blockade of immune cells migratory sensors called chemokine receptors. Specifically, the successful applicant will use a combination of imaging techniques, biochemical and cellular assays for investigations carried out on well-characterized model cell lines to improve our understanding of how microbes impinge on the functions of immune cells.
Background & experiental approach:
Microbial detection by cells of the immune system is paramount for an efficient control of infection. Potentially pathogenic microbes like the Gram+ bacterium S. aureus have developed ways to evade this defense in order to colonize and establish infectious foci leading to disease, but many key aspects of the evasion process remain unknown. S. aureus is the second leading pathogen causing sepsis in industrialized countries1, which underlines the importance of understanding the mechanisms of bacterial evasion and normal host defense.
Innate immune cells detect conserved microbial-associated molecules via cell surface Toll-like receptors (TLRs). Our previous work has shown unusual effects of S. aureus LTA detected by TLR2, blocking cell movement by interfering with cell surface chemokine receptors2. We also established that the functional activity of one of these receptors is affected by its membrane environment3. These findings led us to propose that the plasma membrane delimiting the surface of cells offers a regulatory platform for chemokine receptors.
To test this hypothesis, the PhD will carry out in-cell investigations using model cell lines expressing the LTA receptor TLR2 and the chemokine receptor CCR5. The experimental approach will combine the use of flow cytometry2, laser scanning confocal microscopy3 and cutting-edge total internal reflection fluorescence microscopy4. This will be complemented by standard biochemical experiments (e.g. inhibitions with pharmacological agents, immunoblotting and/or immunoprecipitation) to identify cellular components contributing to the LTA effect.
1 Vogel, M. et al. J Infect 72, 19-28 (2016).
2 Fox, J. M., Letellier, E., Oliphant, C. J. & Signoret, N. Blood 117, 1851-1860 (2011).
3 Fox, J. M., Kasprowicz, R., Hartley, O. & Signoret, N. J Leukoc Biol 98, 59-71 (2015).
4 Gruszka, D.et al . Nature comm. 6, 7271 (2015).
The successful applicant will join the Hull York Medical School and the Department of Biology at the University of York (ranked eighth in the UK for overall performance and first for research impact in REF2014), and will be under the supervision of Dr Nathalie Signoret. This project is integrated in an interdisciplinary Biophysical collaboration with the groups of Dr C. Baumann and Dr M. Fascione from the departments of Biology and Chemistry, respectively. York has a vibrant research student body, meaning the successful applicant will benefit from interactions with a wide variety of other research students. The student will also benefit from a multidisciplinary research environment incorporating the Centre for Immunology and Infection and the Biological Physical Sciences Institute (BPSI) promoting research interface between the Physical and Life Sciences.
We are seeking a highly motivated candidate with an excellent background (first or high upper second class degree, or master’s degree) in immunology, cell biology, biophysics or related discipline. Good analytical skills are essential, as is a strong interest in imaging and microscopy techniques. Applicants must possess excellent oral and written communication skills in English, have good documentation skills, and be willing to take initiative. The studentship covers a stipend at the standard Research Council rate (£14,553 per annum for 2017/18) and tuition fees at the UK/EU rate.
For informal enquiry contact directly Dr Nathalie Signoret.
Applications must be submitted to the HYMS Postgraduate Centre via the online application method (see web page, deadline: 21st April 2017). Please follow the link to apply for PhD in Medical Sciences and include a CV, two academic references, and a personal statement of your research interests (max 500 words) and why you are suited for this project.