Université d’Angers offers a PostDoc position to work on the project “Comparative genomics and metagenomic approaches in patients with cystic fibrosis colonized with Aspergillus fumigatus and treated with triazoles“.

Scientific context:

Progress in the treatment and prevention of bacterial infections over the last three decades, coupled with early diagnosis of the disease and improvement of the nutritional status of patients, has led to a significant increase life expectancy of cystic fibrosis patients. These advances have unfortunately been accompanied by a parallel increase in the frequency of fungal infections. Indeed, the airways of patients are often colonized by filamentous fungi, among which predominate Aspergillus fumigatus; however, unlike bacterial infections, little progress has been made regarding fungal respiratory infections. In particular, the initiation of early antifungal therapy with molecules of the azole family in patients colonized with Aspergillus fumigatus remains controversial in the absence of clinical manifestations. The indications of these antifungals remain imprecise, even contested, because their impact on the virulence of the fungus, the composition of the microbiota and the emergence of resistance is still poorly studied.

Mission (scientific project)

The Antifungal Therapy during Cystic Fibrosis (ATCF) project followed 11 long-term patients with chronic colonization with Aspergillus fumigatus randomized to receive early azole antifungal therapy. This is an international clinical trial that recruited in 2 French centers and 1 English center, promoted by the University Hospital of Rennes, and coordinated by Professor Jean-Pierre GANGNEUX.
The clinical data are now acquired, but the biological material collected during the follow-up of the patients under treatment makes it possible to envisage an ambitious ancillary scientific project, using high-throughput sequencing technologies via comparative genomic and metagenomic approaches. This project will produce new clinical and fundamental data to rationalize azole antifungal therapy in patients with cystic fibrosis.
Three main stages of the project will be declined:

1. Analysis and interpretation of Whole Genome Sequencing of Aspergillus fumigatus isolates. The comparison of the genomes of the different isolates collected during the ATCF study will make it possible to differentiate a re-infestation with a new genotype, the persistence of the same strain in the quiescent state during the treatment and its reactivation when stopped treatment. Similarly, the comparison of sequential isolates from the same patient since the date of the first colonization of the airways will demonstrate the adaptation of the fungus to its host. In both cases, we will look in particular for a genome evolution of these strains affecting genes that can influence antifungal sensitivity and virulence.
2. Comparative analysis of phenotypes and genotypes of resistance of Aspergillus fumigatus. The phenotypic analysis will be carried out by determination of the minimum inhibitory concentrations in agar medium with the E-test® technique, and the results will be correlated with the gene sequence data known to confer resistance to different azole antifungals, but also other genes potentially involved in lower sensitivity to azole antifungals.
3. Metagenome analysis (targeted at the microbiota and mycobiota). The evolution of the metagenome during patient follow-up will be analyzed from the sputum collected in the ATCF study.

Required profile

• Doctor of Science with strong bioinformatics skills,
• a maximum of 3 years’ experience after obtaining a doctorate,
• international research experience (during or after her/his PhD),
• was not supported for the thesis by the recruiting institution and has never worked in the host research unit.
• must have proven experience in the bioinformatics analysis of genomic and metagenomic data in microorganisms and the handling of assignment software
• will have to work directly with the biologists of the two partner laboratories for an optimal exploitation of the sequences and metagenome data, and in particular the correlation with the clinical and microbiological data collected in the initial ATCF study.