The aim of this study was to analyze the transcriptome of A. fumigatus throughout a disseminated infection in order to determine how the fungus deals with the host environment once the infection has been established.
Three independent murine infections were performed intravenously, being one infected kidney from each day used for RNA isolation. RNA samples were hybridized with a customized A. fumigatus expression microarray. Transcriptomic data were compared with a previous study of the germination of this pathogen at 37ºC (Sueiro-Olivares et al., 2015) and results were validated by RT-qPCR. Finally, gene expression changes were analyzed and classified according to their biological function.
Statistical analysis of each day of infection using the A. fumigatus germination at 37ºC as the control condition showed that 4,080, 377, 3,604 and 1,645 genes were differentially expressed on day 1, 2, 3 and 4 of infection, respectively. According to our results, metal metabolism showed down-regulation during the infection. In iron metabolism, different transcription factors involved in siderophore biosynthesis as well as other siderophore production genes (sidA, sidC, sidD) and iron transporters were down-regulated. Something similar was observed in zinc metabolism, in which exporters, importers and even the transcription factor zafA reduced their expression during the infection. On the contrary, gliotoxin biosynthesis pathway stood out as several genes appeared up-regulated throughout the infectious process.
It seems that once A. fumigatus infection has established in the host, a reduction of iron and zinc requirements takes place, questioning the choice of these metabolic routes for developing therapeutic and diagnostic strategies, given that they appear to be useful only when the infection is beginning but not once the invasive aspergillosis is established. Nevertheless, gliotoxin biosynthesis seems to be an indispensable pathway for extending the infection, underlining the necessity of increasing the knowledge of this toxin and its use as antifungal and diagnostic target.
Supported by the UPV/EHU (PES13/03, GIU12/44 and UFI11/25), the Government of the Basque Country (grants S-PC11UN007), and the Ministry of Economy and Competitiveness (MICINN CSD2009-00006). M Sueiro-Olivares and X Guruceaga have been supported by Pre-doctoral Research Grants of the Government of the Basque Country and a Jesús Gangoiti Barrera Foundation grant, respectively.