SltA, a C2H2 zinc finger transcription factor, is highly conserved in Aspergilii with no identifiable homolog in yeast-like fungi. Previous studies verified that SltA prevents toxicity by the cations Na+, K+, Li+, Cs+ and Mg2+ but shows growth defects in the limited extracellular Ca2+ addition in model filamentous fungus Aspergillus nidulans. Here, we demonstrated that SltA homolog in human fungal pathogen A. fumigatus has consistent functions with that of A. nidulans for cation detoxification and calcium auxotrophy such that deletion of AfsltA causes hypersensitive to calcium chelator EGTA while addition of calcium is able to rescue growth defects. The amplitudes of the [Ca2+]c transients are reduced by 33% in AfsltA mutant compared to the parental strain which may result from overexpression of putative vacuolar Ca2+-ATPases PmcA, PmcB and PmcC. Interestingly, deletion of AfsltA has the reduced ergosterol content under itraconazole treatment and shows hypersensitive to antifungals itraconazole, voriconazole, bifonazole and terbinafine in a calcium supplementation independent way but displays no detectable phenotypes to amphotericin B and caspofungin. Furthermore, adding hemin to media or overexpressed cyp51A is able to rescue azoles susceptibilities, suggesting AfsltA may affect ergosterol-biosynthesis functions. Most importantly, Galleria mellonella larvae virulence test shows a significantly attenuated pathogenicity in the AfsltA deletion strain, indicating that AfSltA has unexplored important functions in human pathogens.
Full conference title:
- Fungal Genetics Conference 30th (2019)