Arginine Auxotrophy Affects Siderophore Biosynthesis and Attenuates Virulence of Aspergillus fumigatus
Open Access
- 15 April 2020
- Vol. 11 (4), 423
- https://doi.org/10.3390/genes11040423
Abstract
Aspergillus fumigatus is an opportunistic human pathogen mainly infecting immunocompromised patients. The aim of this study was to characterize the role of arginine biosynthesis in virulence of A. fumigatus via genetic inactivation of two key arginine biosynthetic enzymes, the bifunctional acetylglutamate synthase/ornithine acetyltransferase (argJ/AFUA_5G08120) and the ornithine carbamoyltransferase (argB/AFUA_4G07190). Arginine biosynthesis is intimately linked to the biosynthesis of ornithine, a precursor for siderophore production that has previously been shown to be essential for virulence in A. fumigatus. ArgJ is of particular interest as it is the only arginine biosynthetic enzyme lacking mammalian homologs. Inactivation of either ArgJ or ArgB resulted in arginine auxotrophy. Lack of ArgJ, which is essential for mitochondrial ornithine biosynthesis, significantly decreased siderophore production during limited arginine supply with glutamine as nitrogen source, but not with arginine as sole nitrogen source. In contrast, siderophore production reached wild-type levels under both growth conditions in ArgB null strains. These data indicate that siderophore biosynthesis is mainly fueled by mitochondrial ornithine production during limited arginine availability, but by cytosolic ornithine production during high arginine availability via cytosolic arginine hydrolysis. Lack of ArgJ or ArgB attenuated virulence of A. fumigatus in the insect model Galleria mellonella and in murine models for invasive aspergillosis, indicating limited arginine availability in the investigated host niches.This publication has 49 references indexed in Scilit:
- Characterization of the Link between Ornithine, Arginine, Polyamine and Siderophore Metabolism in Aspergillus fumigatusPLOS ONE, 2013
- The GATA factors AREA and AREB together with the co-repressor NMRA, negatively regulate arginine catabolism in Aspergillus nidulans in response to nitrogen and carbon sourceFungal Genetics and Biology, 2012
- HapX-Mediated Adaption to Iron Starvation Is Crucial for Virulence of Aspergillus fumigatusPLoS Pathogens, 2010
- Evaluation of Lysine Biosynthesis as an Antifungal Drug Target: Biochemical Characterization of Aspergillus fumigatus Homocitrate Synthase and Virulence StudiesEukaryotic Cell, 2010
- Arginine metabolism and nutrition in growth, health and diseaseAmino Acids, 2008
- SreA‐mediated iron regulation in Aspergillus fumigatusMolecular Microbiology, 2008
- Role of laeA in the Regulation of alb1 , gliP , Conidial Morphology, and Virulence in Aspergillus fumigatusEukaryotic Cell, 2007
- A twin-reporter vector for simultaneous analysis of expression signals of divergently transcribed, contiguous genes in filamentous fungiGene, 1991
- Determination of amino acid sequences involved in the processing of the ARG5/ARG6 precursor in Saccharomyces cerevisiaeJBIC Journal of Biological Inorganic Chemistry, 1991
- The effects of specific auxotrophic mutations on the virulence of Aspergillus nidulans for miceMycopathologia, 1973