The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

Abstract

Aspergillus fumigatus is the predominant airborne pathogenic fungus causing invasive aspergillosis in immunocompromised patients. During infection A. fumigatus has to adapt to oxygen-limiting conditions in inflammatory or necrotic tissue. Previously, we identified a mitochondrial protein to be highly up-regulated during hypoxic adaptation. Here, this protein was found to represent the novel oxidoreductase HorA. In Saccharomyces cerevisiae a homologue was shown to play a role in biosynthesis of coenzyme Q. Consistently, reduced coenzyme Q content in the generated ΔhorA mutant indicated a respective function in A. fumigatus. Since coenzyme Q is involved in cellular respiration and maintaining cellular redox homeostasis, the strain ΔhorA displayed an impaired response to both oxidative and reductive stress, a delay in germination and an accumulation of NADH. Moreover, an increased resistance against antifungal drugs was observed. All phenotypes were completely reversed by the addition of the synthetic electron carrier menadione. The deletion strain ΔhorA showed significantly attenuated virulence in two murine infection models of invasive pulmonary aspergillosis. Therefore, the biosynthesis of coenzyme Q and, particularly, the fungal-specific protein HorA play a crucial role in virulence of A. fumigatus. Due to its absence in mammals, HorA might represent a novel therapeutic target against fungal infections.

Ecology of aspergillosis: insights into the pathogenic potency of Aspergillus fumigatus and some other Aspergillus species

“…Aspergillus fischeri and Aspergillus oerlinghausenensis (Houbraken et al ., ) – do not typically behave as opportunistic pathogens. Is it because A. fumigatus is more widely spread in the environment, can enter the human host and evade the immune system more successfully, grows well at 37°C or is it better adapted to microenvironments such as the human body that are often characterized by low nutrient and oxygen availability (Tables and ; Hall and Denning, ; Hillmann et al ., ,b; Kroll et al ., in press)? A. fumigatus , in particular, and aspergilli in general are very highly evolved and successful soil saprophytes and the competition they face in the soil environment has provided some species or strains most probably with the ability to colonize and cause disease in a compromised human or animal host upon entering the lungs (Tekaia and Latgé, ).…”

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…83,84 Most recently, the signal peptide peptidase SppA, the protease RbdA, and the hypoxia-induced dehydrogenase HorA have also been linked to hypoxia adaptation and virulence, possibly through interactions with the Srb pathways. 80,85,86 Together these data suggest a model whereby the ability of A. fumigatus to thrive in hypoxic microenvironments is a critical factor in the pathogenesis of IA and suggest a potential role for hyperbaric oxygen therapy for IA in HSCT patients.…”

Redox Proteomic Analysis Reveals Oxidative Modifications of Proteins by Increased Levels of Intracellular Reactive Oxygen Species during Hypoxia Adaptation of Aspergillus fumigatus

“…The generated mutants were verified by Southern blot (Figure S2, Supporting Information) as described in ref. . The gene specific DNA probe was generated by PCR using the primers P1 and P3.…”