(MRC DTP) Investigating the role of long distance signalling in the synergistic virulence of Aspergillus fumigatus — Pseudomonas aeruginosa co-infection.

It is recognised that intermicrobial interactions in human tissues are of paramount importance for homeostasis and health, and it is clear that these interactions may lead to disease. In infectious diseases in particular, interactions between microorganisms are expected to have a great impact on the outcome of infection.

Aspergillus fumigatus is the most common fungal pathogen and Pseudomonas aeruginosa one of the most prevalent bacterial pathogens of the human lung. These microbes are commonly found in long term pulmonary disorders such as chronic obstructive pulmonary disease or cystic fibrosis. In fact, A. fumigatus and P. aeruginosa are the most prevalent fungal and bacterial pathogens, respectively, isolated from the airways in cystic fibrosis. Co-infection is common and results in an overall worse prognosis for the patient.

When these two microbes co-infect a host it is likely that they interact, which may affect their virulence potential and therefore have an impact on disease outcome. Using an invertebrate model of infection we have described a synergistic association, based on the production of volatile sulphur compounds, that results in enhanced fungal and bacterial burdens in infected organisms and consequently higher mortality (submitted manuscript). Furthermore, using an in vitro infection model with an epithelial cystic fibrosis cell line we have confirmed that co-infection enhances fungal and bacterial growth in infection settings (preliminary results).

The objective of this PhD project is to decipher the mechanisms that underpin the increase of pathogenicity in co-infection. To this aim the student will investigate gene expression patterns of fungal and bacterial cells that are in close proximity, but not in direct contact. We will then scrutinize relevant traits by constructing mutant strains and characterising their virulence potential in single and co-infection using both in vitro and in vivo models of infection. We will further determine which volatile compounds trigger the long distance signalling responsible for the intermicrobial interaction and investigate how such communication can be prevented. Finally, we will explore if those volatiles can be detected in infected patients, which will be the basis for the translation of our results into clinical application.
Therefore, our findings will have the potential to drive the development of novel strategies to manage co-infected patients and also to identify volatile compounds that may serve as biomarkers of co-infection.

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.