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Development of an in vitro model to dissect the mechanism of fungal persistence in the cystic fibrosis lung


Project Description

Cystic fibrosis (CF) is the most common fatal genetically inherited disease in Caucasian populations. This disease is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR) which produces defective ion fluxes and calcium homeostasis in the epithelia. Patients with cystic fibrosis are susceptible to lung infections caused by the fungal pathogen Aspergillus fumigatus.

Animal models play a central role in the study of cystic fibrosis. Researchers have used mice, ferrets, pigs and sheep to model the inflammatory response seen in human patients with this disease. Although such models generate useful knowledge on the pathophysiology of this disease, animal models are limited for a number of ethical reasons.

Here we propose to establish a new in vitro model of isogenic CF and healthy controls bronchial epithelial cell lines carrying different mutations in the CFTR gene using CRISPR/Cas9 mutagenesis. Using an established methodological approach in our laboratory including in vitro infection, confocal microscopy, expression analysis, cytokine measurements and competitive fitness analysis the student will be able to define critical stages of the interaction between the cystic fibrosis epithelia and A. fumigatus compared to healthy cells and the fungal factors governing this process.

The successful completion of this project will achieve a number of scientific objectives. Firstly, the development of an isogenic cell culture system of epithelial cell lines will be of great value for researchers focused on the study of epithelia-pathogen interactions in CF. Secondly, screening of A. fumigatus null libraries on CF epithelia will increase our knowledge on the pathogen factors leading persistence in the context of disease. Additionally, the student will be enrolled in a programme that will give the student the opportunity to enrol with industrial partners in Manchester and our fungal community to promote the implementation on this resource in other laboratories at an international level.

Entry Requirements
Candidates are expected to hold a minimum of a good first degree (upper second class or better) from a UK university or an equivalent qualification if obtained outside the UK in a relevant discipline. A Masters degree or experience in Infection Biology or Microbiology is desirable.

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/). If you are interested, please make direct contact with the Supervisor to discuss the project. You MUST also submit an online application form - choose PhD Medical Mycology.

Funding Notes

This project is funded by National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs). Studentship funding is for a duration of three years to commence in September 2020 and covers UK/EU tuition fees and a UKRI stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Lung colonization by Aspergillus fumigatus is controlled by ZNF77. Gago S, Overton NLD, Ben-Ghazzi N, Novak-Frazer L, Read ND, Denning DW, Bowyer P. Nat Commun. 2018 Sep 20;9(1):3835. doi: 10.1038/s41467-018-06148-7.

Pathophysiological aspects of Aspergillus colonization in disease. Gago S, Denning DW, Bowyer P. Med Mycol. 2019 Apr 1;57(Supplement_2):S219-S227. doi: 10.1093/mmy/myy076. Review.

Aspergillus fumigatus and Aspergillosis in 2019. Latgé JP, Chamilos G. Clin Microbiol Rev. 2019 Nov 13;33(1). pii: e00140-18. doi: 10.1128/CMR.00140-18. Print 2019 Dec 18. Review.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. Iannitti RG, Napolioni V, Oikonomou V, De Luca A, Galosi C, Pariano M, Massi-Benedetti C, Borghi M, Puccetti M, Lucidi V, Colombo C, Fiscarelli E, Lass-Flörl C, Majo F, Cariani L, Russo M, Porcaro L, Ricciotti G, Ellemunter H, Ratclif L, De Benedictis FM, Talesa VN, Dinarello CA, van de Veerdonk FL, Romani L. Nat Commun. 2016 Mar 14;7:10791. doi: 10.1038/ncomms10791.

Inducible Cell Fusion Permits Use of Competitive Fitness Profiling in the Human Pathogenic Fungus Aspergillus fumigatus.
Macdonald D, Thomson DD, Johns A, Contreras Valenzuela A, Gilsenan JM, Lord KM, Bowyer P, Denning DW, Read ND, Bromley MJ. Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01615-18. doi: 10.1128/AAC.01615-18

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