Prof E Bignell, Prof A MacDonald
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Spores of the major mould pathogen of humans, Aspergillus fumigatus (1), are inhaled on a continual basis and pose a unique and complex challenge to human immunity, as management of this pathogenic threat must be finely tuned to avoid inflammation, and damage, of the airway (2). Our in vivo transcriptomic analyses (3) have revealed that germinating fungal spores produce rapidly elongating cells which are able to invade the lung epithelium of immunocompromised hosts and which express a variety of antigenic and toxic components including secondary metabolites, proteases, β-glucan and glycosphingolipid. Defective clearance of inhaled mould spores leads to rapidly fatal invasive lung infection in cancer and organ transplant patients, chronic lung infection in tuberculosis and COPD sufferers and severe, life-threatening, allergic disease in asthmatics and cystic fibrosis sufferers.
This research will exploit powerful new approaches to selectively modulate both host and pathogen activities contributing to initiation of type 2 inflammation (4) in response to inhaled spores. As well as addressing fundamental questions on the molecular basis of type 2 inflammatory disease, this research will also address the therapeutic relevance of selectively depleting deleterious fungal antigen production in the setting of airway disease.
Three key technologies will be exploited:
a) Adoptive transfer of antigen-conditioned dendritic cells to study orchestration of inflammatory responses in naive hosts (5)
b) Differential conditioning of dendritic cells in vitro and in vivo by selective depletion of key antigenic stimuli in transgenic moulds
c) Ultra-high resolution of host-pathogen transcriptomics using laser microdissection and next generation RNA sequencing technology
This project forms part of our 2014 MRC Doctoral Training Partnership (DTP). Due to commence October 2014, the studentship provides full support for tuition fees and a tax-free annual stipend at Research Council rates (currently £13, 726).
Applicants should initially contact the primary supervisor (link below) to discuss the project and their suitability. If encouraged, an online application must then be submitted, selecting “MRC DTP Studentship” on the University online application form.
http://www.manchester.ac.uk/postgraduate/howtoapply/
Further guidance on the application process can be accessed here: http://www.mhs.manchester.ac.uk/postgraduate/studentships/mrcdtp/
Deadline for applications: 6 December 5pm.
Interviews for shortlisted candidates: 13/14 January 2014.
Further information:
Primary Supervisor: Elaine Bignell http://www.inflammation-repair.manchester.ac.uk/staff/157924
Follow us: https://twitter.com/GradSch_MHS_UoM
http://www.mhs.manchester.ac.uk/postgraduate/
http://www.mhs.manchester.ac.uk/postgraduate/studentships/
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Funding Notes
This project is open to UK/EU nationals only due to the nature of the funding.
References
References:
1) Latge, J P (1999) Aspergillus fumigatus and Aspergillosis Clin. Microbiol. Rev. 12:310-350
2) McDonagh, A. et al (2008) Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog, 4(9), e1000154.
3) Romani, L. (2011) Immunity to fungal infections. Nat. Rev. Immunol. 11:275-288
4) Pulendran, B. and Artis, D. (2012) New Paradigms in type 2 immunity. Science. 337:431-435
5) Cook, P et al (2012). Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo. Proc Natl Acad Sci U S A, 109: 9977-9982.
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