Abstract
The human pathogenic fungus Aspergillus fumigatus is readily eradicated by the innate immunity of immunocompetent human hosts, but can cause severe infections, such as invasive aspergillosis (IA), in immunocompromised individuals. During infection, the fungal redox homeostasis can be challenged by reactive oxygen species (ROS), either derived from the oxidative burst of innate immune cells or the action of antifungal drugs. The peroxiredoxin Asp f3 was found to be essential to cause IA in mice, but how Asp f3 integrates with fungal redox homeostasis remains unknown. Here, we show that in vivo, Asp f3 acts as a sensor for ROS. While global transcription in fungal hyphae under minimal growth conditions was fully independent of Asp f3, a robust induction of the oxidative stress response required the presence of the peroxiredoxin. Hyphae devoid of Asp f3 failed to activate several redox active genes, like members of the gliotoxin biosynthesis gene cluster and integral members of the Afyap1 regulon, the central activator of the ROS defense machinery in fungi. Upon deletion of the asp f3 gene Afyap1 displayed significantly reduced nuclear localization during ROS exposure, indicating that Asp f3 can act as an intracellular redox sensor for several target proteins.
Highlights
IntroductionAccepted: 27 April 2021The ascomycete Aspergillus fumigatus is a ubiquitous fungus which is generally involved in the decomposition of (plant based) biomass, playing an important role during carbon and nitrogen recycling [1,2]
Accepted: 27 April 2021The ascomycete Aspergillus fumigatus is a ubiquitous fungus which is generally involved in the decomposition of biomass, playing an important role during carbon and nitrogen recycling [1,2]
We found Asp f3 to be the peroxiredoxin that mediates nuclear retention of Afyap1 under reactive oxygen species (ROS) exposure in A. fumigatus, indicating that this function may well be conserved for its homologue in A. nidulans-PrxA, which was found to be involved in oxidative stress defense and suspected to be the regulatory peroxiredoxin for NapA [49,53]
Summary
Accepted: 27 April 2021The ascomycete Aspergillus fumigatus is a ubiquitous fungus which is generally involved in the decomposition of (plant based) biomass, playing an important role during carbon and nitrogen recycling [1,2]. With its ability to adapt to a wide temperature range, different oxygen and pH levels and nutritional challenges like low iron levels, A. fumigatus thrives in many diverse environments and is known as the most common airborne fungal pathogen. Infection occurs via the widely distributed asexual conidia which after inhalation, germinate and colonize the lung tissue of immuno-compromised patients such as those suffering from HIV, leukemia or active therapeutic immunosuppression following organ and stem cell transplantation [3,4]. Depending on the underlying condition infections range from allergic bronchopulmonary aspergillosis (ABPA) to often fatal invasive aspergillosis (IA), a disease reaching mortality rates in the range of 30–95% [5,6]. Reasons for high mortality are deficiencies in specific and timely diagnostics as well as the limited availability of effective therapeutic treatment [7]. It is imperative to aim for a better understanding of the pathophysiology of A. fumigatus, enabling more targeted approaches towards the development of new therapeutic solutions
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