Lipidomic-focused mass spectrometry of Aspergillus fumigatus mutant strains aiming to understand the relationship between thermotolerance, cell wall integrity and cell membrane lipid composition

Abstract

Aspergillus fumigatus is a major opportunistic pathogen of mammals and the main causative pathogen of invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. Thermotolerance is one of the key virulence determinants of this fungus, being a prerequisite for the establishment of infection and persistence of the pathogen inside the host. The data obtained so far in our laboratory suggest that the HsfA transcription factor is one of the most important regulators of the heat shock response in this organism due to its essentiality and broad range of downstream transcriptional targets. It is known, that there is an interplay between heat shock response genes and the maintenance of the cell wall integrity (CWI) in yeast and other fungal pathogens, such as Candida albicans. Moreover, in response to temperature shock, fungal organisms trigger different adaptive responses such as that governing the cell membrane homeostasis towards distinct lipid composition and fluidity. For instance, the stearoyl-CoA desaturase enzyme, encoded by the sdeA gene (yeast OLE1 homologue) which catalyzes the monounsaturated fatty acid synthesis, seems to be related to thermotolerance. Thus, analysis of the lipid composition of A. fumigatus mutant strains for the hsfA, sdeA and CWI pathway genes (such as pkcA, mpkA and rlmA), in the presence of temperature and cell wall stress, could provide important knowledge about the role of these genes and the effect of thermotolerance on cell membrane homeostasis. This project will complement previous studies in our laboratory on thermotolerance and cell wall integrity and can provide useful information for potential antifungal therapies and how A. fumigatus respond to heat and cell wall stresses. (AU)