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

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.