Arginine Auxotrophy Affects Siderophore Biosynthesis and Attenuates Virulence of Aspergillus fumigatus

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.

Genomic Insights Into the Interspecific Diversity and Evolution of Mobiluncus, a Pathogen Associated With Bacterial Vaginosis

“…We also detected a series of metabolic pathways that showed apparent species specificity, most of which have been reported to be associated with virulence and adoption of pathogenic organisms. For example, the role of arginine biosynthesis in virulence has been reported to be crucial for full virulence of Aspergillus fumigatus in insects ( Dietl et al, 2020 ), and we have showed that the pathway of arginine biosynthesis in M. curtisii and M. mulieris was different, perhaps suggesting a different utilizing efficiency. Furthermore, the capabilities of MoCo biosynthesis and nitrate reduction were only found in M. curtisii strains, both of which have been implicated in pathogenesis of a number of bacterial infections ( Williams et al, 2011 ; Andreae et al, 2014 ; Almeida et al, 2017 ); more his genes were found in M. curtisii strains, perhaps enabling them capacity of biosynthesis of histidine and a crucial role in metal homeostasis and virulence ( Dietl et al, 2016 ); and the extra NAD + de novo biosynthesis pathway in M. curtisii could also enhance their virulence during host infection ( Dom and Haesebrouck, 1992 ; Wang et al, 2019 ).…”

AhrC Negatively Regulates Streptococcus mutans Arginine Biosynthesis

“…3B ). It is reported that the bifunctional argJ has been found in Aspergillus fumigatus , Saccharomyces cerevisiae , and Thermophilic microorganisms ( 35 – 37 ). The present study showed that ahrC deletion significantly upregulated argB , argC , argD , argF , argJ , argG , and argH , indicating that ahrC is closely associated with the S. mutans arginine biosynthesis pathway.…”

Aspartate Transaminase AST2 Involved in Sporulation and Necrotrophic Pathogenesis in the Hemibiotrophs Magnaporthe oryzae and Colletotrichum graminicola

“…The glutamate family includes glutamate and other derived glutamine, proline, and arginine from glutamate; and lysine sometimes is included in this family. The biosynthesis of glutamate and glutamine is a key step in the nitrogen assimilation ( Kwan et al, 2015 ; Dietl et al, 2020 ). Generally, the enzymes glutamine oxoglutarate aminotransferase and glutamate dehydrogenase catalyze the nitrogen assimilation reactions.…”