About the Project
Background
Familial Mediterranean Fever (FMF) is a rare inherited genetic disease where patients acquire a mutation on the pyrin gene leading to excessive inflammasome activation and excessive inflammation. Patients experience recurrent fevers and pain in their abdomen, chest, and joints. It predominantly affects Arab, Jewish, Turkish, and Armenian ethnic minorities. Asymptomatic carriers are thought to have had a survival advantage in previous bubonic plague (Yersinia pestis) pandemics. However, these patients are hard to diagnoses and little is known about their responses to infection or anti-IL biologics.
Aims
The aims of this study are: (1) To develop novel immune diagnostic tests in FMF patients where genetics revealed only a single MEFV gene variant being able to identify asymptomatic carriers; and (2) To evaluate the ability of FMF carriers and patients’ blood cells to restrict growth of live Yersinia species compared with healthy controls, and the direct role of inflammatory cytokines in the containment of plague bacteria using anti-IL-1 biologics.
Methods
Peripheral blood neutrophils and monocytes from healthy controls, FMF gene carriers and symptomatic FMF patients will be isolated and tested for pyrin inflammasome activation in vitro using Yersinia toxins, as well as other existing activators, and Yersinia infection (Y. enterocolitica, Y. pseudotuberculosis). Pyrin inflammasome activation (cell death, caspase-1 activity, and cytokine release via ELISA) will be assayed before and after addition of anti-IL-1 biologics as well as the ability of immune cells to contain infection.
Impact
Development of novel single cell diagnostics will avoid delays and missed diagnosis in heterozygous patients where MEFV genetic screening is inadequate. In vitro tests of bacterial containment with and without addition of anti-IL-1 biologics will provide direct evidence of the ability of FMF gene carriage to protect against Yersinia, including bubonic plague infections.
The student will acquire a variety of skill relating to bacterial and human cell culture, genomic and proteomic techniques, and data analysis.
Training/techniques to be provided
The student will receive training in the following techniques:
- Human cell culture
- Bacterial cell culture
- ELISA
- FACS
- Cell death assays
- Caspase-1 assays
- Western blots
Entry Requirements
Candidates are expected to hold (or be about to obtain) a minimum 2.1 (or equivalent) in a related area / subject i.e. BSc Immunology, BSc Microbiology, BSc Cell Biology. Ideally, candidates will have an MSc in one of these areas too. Laboratory experience in human cell culture and ELISA would be an advantage. Candidates must also meet English language requirements (IELTS score of at least 6.5, with a 6 in writing, or equivalent), read more here: English language requirements | International | The University of Manchester.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the programme PhD Immunology.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk
Equality, Diversity & Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
References
2.Park, Y. H., Remmers, E. F., Lee, W., et al. (2020) Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat. Immunol. 21, 857–867 DOI: 10.1038/s41590-020-0705-6
3. Van Gorp H, Huang L, Saavedra P, et al. Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever. Ann Rheum Dis 2020;79:960-968. DOI: 10.1136/annrheumdis-2019-216701
4. Magnotti F, Malsot T, Georgin-Lavialle S, et al. Fast diagnostic test for familal Mediterranean fever based on a kinase inhibitor. Ann Rheum Dis 2021;80:128-132. DOI: 10.1136/annrheumdis-2020-218366
5. Medici, NP, Rashid M, Bliska JB. (2019) Characterization of Pyrin Dephosphorylation and Inflammasome Activation in Macrophages as Triggered by the Yersinia Effectors YopE and YopT. Infect. Immun. 10.1128/IAI.00822-18. DOI: 10.1128/IAI.00822-18
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