Institute of Molecular Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Institute of Hygiene & Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Genes (Basel). 2020 Apr 15;11(4):423. doi: 10.3390/genes11040423.
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 via genetic inactivation of two key arginine biosynthetic enzymes, the bifunctional acetylglutamate synthase/ornithine acetyltransferase (/AFUA_5G08120) and the ornithine carbamoyltransferase (/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 . 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 in the insect model and in murine models for invasive aspergillosis, indicating limited arginine availability in the investigated host niches.
是一种机会性人类病原体，主要感染免疫功能低下的患者。本研究的目的是通过遗传失活两种关键的精氨酸生物合成酶，双功能乙酰谷氨酸合酶/鸟氨酸乙酰转移酶（/AFUA_5G08120）和鸟氨酸氨甲酰转移酶（/AFUA_4G07190），来描述精氨酸生物合成在 中的毒力作用。精氨酸生物合成与鸟氨酸的生物合成密切相关，鸟氨酸是铁载体产生的前体，先前的研究表明铁载体的产生对于在 中的毒力至关重要。ArgJ 特别有趣，因为它是唯一缺乏哺乳动物同源物的精氨酸生物合成酶。ArgJ 或 ArgB 的失活导致精氨酸营养缺陷。缺乏 ArgJ，这对于线粒体鸟氨酸生物合成是必需的，在以谷氨酰胺为氮源的有限精氨酸供应下，显著降低了铁载体的产生，但以精氨酸为唯一氮源时则没有。相比之下，在 ArgB 缺失菌株中，无论在何种生长条件下，铁载体的产生都达到了野生型水平。这些数据表明，在有限的精氨酸供应下，铁载体生物合成主要由线粒体鸟氨酸产生提供燃料，但在高精氨酸供应下则由细胞质精氨酸水解提供燃料。ArgJ 或 ArgB 的缺乏削弱了 在昆虫模型 和侵袭性曲霉病的小鼠模型中的毒力，表明在研究的宿主小生境中精氨酸的可用性有限。
