The impact of nutritional scavenging on host-pathogen interactions, antifungal efficacy and emergence of antifungal resistance

Infections caused by Aspergillus fumigatus (Af) cause more deaths globally than any other fungal disease. Over 20 million are affected annually with four million having life threatening invasive and chronic infections with high morbidity and mortality up to 90%. Aspergillus research is vastly underfunded compared to other diseases causing similar numbers of deaths per year.

There are only three classes of antifungals currently in widespread use to treat aspergillosis. Of these, only the triazoles are available as oral formulations and hence suitable for long term treatment. However, antifungal resistance is on the rise and hampers our ability to effectively treat these diseases. Despite the drastic need for novel antifungal, the development pipeline has stalled since the early 2000s, with no new antifungals available for systemic diseases.

Developing novel antifungals has proven difficult, as fungal specific targets are sparse and screening for novel compounds is technically challenging, with in vitro screening settings often only poorly mimicking in vivo conditions. Our recent data has shown that host epithelial cells provide a nutritional source for Af, with Af mutants otherwise severely impacted for growth able to sustain their growth in vitro in the presence of host cell lysates. However, we currently have a limited understanding of the nutritional conditions experienced by the fungus in vitro and importantly during mammalian lung invasion and how essential nutrients are scavenged by Af to its benefit.

We hypothesise that a better understanding of nutrient scavenging in vitro and in vivo will benefit our ability to model fungal infection in vivo, antifungal efficiency testing. To this end, this project aims to pinpoint which are the nutrients scavenged by Af through functional and genomic analyses of in vitro and in vivo Af infection.

This knowledge will be translated to develop a new medium that represents the nutritional environment during infection and develop a high throughput screening method that allows for the screening of novel antifungals in a more infection-relevant setting and identify potential antifungal compounds that would otherwise remain unexplored.

The project proposed is highly interdisciplinary and links the Manchester Fungal Infection Group with MERMan. The projects spans Fungal Genetics, Infection Biology and Antifungal Development with the ultimate aim to develop a novel medium for antifungal screening with the potential to identify novel antifungal that are currently overlooked due to poor in vitro efficacy.

Techniques and training provided will consists of:

Handling of large collections of isolates

Genetic manipulation of fungi including CRISPR-Cas9 mediated transformations

Performing a wide range of phenotypic characterisation experiments

Handling, maintenance and infection of mammalian cell lines with A. fumigatus

Preparation of cell culture lysates

In vitro assays to measure fungal killing, host cell killing, fungal uptake, intracellular fungal killing and cytokines release. 

High throughput phenotyping

Susceptibility testing

In vitro evolution experiments

Fluctuation assays

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject area.

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 the PhD Infection, Immunity and Respiratory Medicine.

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 https://www.bmh.manchester.ac.uk/study/research/international/

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