Abstract
Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals.Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches.
Highlights
Aspergillus fumigatus is the most common air-borne human fungal pathogen, causing the life-threatening disease invasive aspergillosis, in immunocompromised patients.[1]
To analyze the role of histidine biosynthesis in A. fumigatus, we generated a mutant strain lacking HisB, termed DhisB, by replacement of the encoding gene hisB with the hygromycin resistance hph cassette as described in Material and Methods and Fig. S2
DhisB, and hisBC strains in liquid media and on plates (Fig. 1A) demonstrated that HisB-deficiency causes histidine auxotrophy in A. fumigatus as previously shown in A. nidulans.[4,13]
Summary
Aspergillus fumigatus is the most common air-borne human fungal pathogen, causing the life-threatening disease invasive aspergillosis, in immunocompromised patients.[1] Depending on the immune status and other factors in the patients, mortality rates in connection with invasive aspergillosis range from 60–90%, largely due to poor therapeutic interventions and only limited specific diagnostic methods available.[2] Novel antifungal therapy approaches aim to target fungal-specific pathways that are essential for virulence. One such potential pathway is the biosynthesis of histidine.
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