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How does Aspergillus fumigatus activate the inflammasome?


   Faculty of Biology, Medicine and Health


Manchester United Kingdom Biochemistry Bioinformatics Cell Biology Genetics Microbiology Molecular Biology

About the Project

Invasive fungal infections are a major cause of mortality, with more people dying from the ten main invasive fungal diseases than from tuberculosis or malaria. Despite the development of new antifungal drugs and medical procedures, mortality rates for these diseases remain extremely high. This is the case of fungal lung infections caused by the opportunistic mould Aspergillus fumigatus for which mortality can reach 90%.

A.fumigatus is a saprophytic mould which produces millions of small conidia (2–3 μm) that are released into nearly all human accessible habitats. The innate immune system provides the first line of defence against inhaled A. fumigatus conidia. Recognition of A. fumigatus by the host immune system leads to activation of the inflammasome, which provides protection against infection. It has been shown that structural components on the cell wall of Aspergillus conidia called beta glucans can trigger inflammasome activation. Additionally, inflammasome responses during fungal infections caused by Candida species relies upon morphological transformation to its hyphal appearance in a process driven by the release of a toxin called candidalysin. However, the specific hyphal factors that enable A. fumigatus to activate the inflammasome in macrophages remain to be revealed.

The aim of this project is to identify Aspergillus fumigatus factors that contribute to inflammasome activation. The Manchester Fungal Infection Group has developed the first-in-field genome wide knock out library of A. fumigatus. The candidate will screen A. fumigatus knock out mutants in genes we have previously defined as virulence factor, for inflammasome activation in macrophages using an in vitro model of disease. Defining Aspergillus hyphae-derived drivers of inflammasome response in macrophages will allow us to better understand the fungal mechanisms that determine the pathogenity of A. fumigatus and contribute to de discovery of new drug targets.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.

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 PhD Genetics

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.

Equality, Diversity and 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/”

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


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

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

Bongomin F et al. Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J Fungi (Basel). 2017 Oct 18;3(4):57. doi: 10.3390/jof3040057.

Furukawa T et al. The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus. Nat Commun. 2020 Jan 22;11(1):427. doi: 10.1038/s41467-019-14191-1.

Briad B et al. Fungal ligands released by innate immune effectors promote inflammasome activation during Aspergillus fumigatus infection. Nat Microbiol. 2019 Feb;4(2):316-327. doi: 10.1038/s41564-018-0298-0.

Rogiers et al. Candidalysin Crucially Contributes to Nlrp3 Inflammasome Activation by Candida albicans Hyphae. mBio 2019 Jan 8;10(1):e02221-18. doi: 10.1128/mBio.02221-18.

Lopez-Castejon G. Control of the inflammasome by the ubiquitin system. FEBS J. 2020 Jan;287(1):11-26. doi: 10.1111/febs.15118.


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