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(A*STAR) Unravelling the metabolic basis of Aspergillus fumigatus adaptation to combinatorial stress conditions


Project Description

Aspergillus fumigatus is an environmental saprophytic fungus that lives ubiquitously in the soil. This fungus can also infect the lungs of individuals with any kind of immune imbalance, causing a broad range of diseases collectively termed aspergillosis. In immunocompromised patients it can cause invasive pulmonary aspergillosis, a disease with an extremely high mortality rate (50-90%, depending on time of diagnosis). The efficacy of current treatments is limited by the low number of antifungals in clinical use (there are only three classes available: azoles, echinocandins and polyenes) and a worrisome world-wide emergence of antifungal resistance. To be able thrive in the human airways A. fumigatus must be able to adapt to the combination of all types of stresses imposed by the host, including nutrient limitation, oxidative stress or hypoxia. This capacity to deal with and counteract stress is known to be essential for pathogenicity and has been proposed could be targeted for the development of novel antifungal drugs. So far the adaptation to host imposed stresses has been investigated separately, which has led to the identification of key regulators and effectors for each of them. However, it is known that combinatorial stress has a different and more severe effect on organisms than each of the single stresses. Therefore, it is expectable that adaptation to a combination of stresses is more complex than just the addition of the single responses. To tackle that complexity, we will develop a genome-scale metabolic model of A. fumigatus and combine it with multi –omics data to run in silico analyses that can detect novel, non-obvious, mechanisms of adaptation to combinatorial stress. We will then test the identified traits by constructing mutant strains and investigating the consequences of their impairment for A. fumigatus virulence using phenotypic, transcriptional and infection studies. Our project has the potential to pave the way to a more complete understanding of pathogen adaptation to host conditions and to identify novel virulence mechanisms that overlap among various metabolic pathways and can be exploited for the development of better antifungal drugs.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on 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

1. Amich J. mSphere of Influence: the importance of metabolism for pathogen adaptation to host-imposed stresses. 2019. mSphere4:e00566-19.https://doi.org/10.1128/mSphere.00566-19.
2. Vicentefranqueira R, Amich J, Marín L, Sánchez CI, Leal F, Calera JA. The Transcription Factor ZafA Regulates the Homeostatic and Adaptive Response to Zinc Starvation in Aspergillus fumigatus. Genes (Basel). 2018 Jun 26;9(7). pii: E318. doi: 10.3390/genes9070318.
3. Amich J and Bignell E. Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more? Curr Opin Microbiol. 2016 Aug;32:151-8.
4. Amich J, Schafferer L, Haas H and Krappmann S. Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus. PLoS Pathog. 2013; 9(8):e1003573.
5. Amich J and Krappmann, S. Deciphering metabolic traits of the fungal pathogen Aspergillus fumigatus: redundancy vs. essentiality. Front. Microbio. 2012 Dec. 3;3:414.

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