Study of the Aspergillus fumigatus host-pathogen interaction using transcriptomic techniques and mutant strains generation

Abstract

Aspergillus fumigatus is a filamentous fungus capable to cause a wide range of diseases depending on the immune status of the patient who breath its conidia. The most dangerous disease caused by this fungus is known as invasive aspergilosis and its diagnosis and treatment is frequently delayed and useless. Therefore, describing new virulence factors that could serve as new diagnostic or therapeutic targets is crucial. In this PhD thesis, we have designed a whole genome transcriptomic study in different infection conditions with the aim to define which Aspergillus fumigatus genes are differentially expressed during the infective process. The project is divided in three related chapters in which we have defined genes that could be important for the establishment and development of the Aspergillus fumigatus infection. Specifically, we have found that during the first 96 hours of an intranasal infection, the genes related with the biosynthesis of fumagillin/pseurotina, several genes that codify proteases (dppIV, dppV, aspf1 or aspf5), chitinase (chiB1) as well as some genes related with pyomelanin biosynthesis (hppD and maiA) are overexpressed. Furthermore, we have described that fumagillin could be an important virulence factor for the fungus because this mycotoxin causes cell death and inhibition of the cell metabolism and proliferation. In the same way, the toxin is a protective factor against phagocytosis and plays an important role during the infection process. Finally, using CRISPR-Cas9 technology we have proved that Aspergillus fumigatus maiA gene is involved in the fungal cell wall synthesis, the correct hyphae development and the fungal virulence.