Abstract
The identification of cellular targets for antifungal compounds is a cornerstone for the development of novel antimycotics, for which a significant need exists due to increasing numbers of susceptible patients, emerging pathogens, and evolving resistance. For the human pathogenic mold Aspergillus fumigatus, the causative agent of the opportunistic disease aspergillosis, only a limited number of established targets and corresponding drugs are available. Among several targets that were postulated from a variety of experimental approaches, the conserved thioredoxin reductase (TrxR) activity encoded by the trxR gene was assessed in this study. Its essentiality could be confirmed following a conditional TetOFF promoter replacement strategy. Relevance of the trxR gene product for oxidative stress resistance was revealed and, most importantly, its requirement for full virulence of A. fumigatus in two different models of infection resembling invasive aspergillosis. Our findings complement the idea of targeting the reductase component of the fungal thioredoxin system for antifungal therapy.
Highlights
Fungi as infectious agents of man pose a constant threat to a specific cohort of individuals, mainly immunosuppressed patients and people living in areas being endemic for primary fungal pathogens (Brown et al, 2012; Köhler et al, 2017)
The A. fumigatus Trx/thioredoxin reductase (TrxR) system became of interest due to limited structural similarity with the human orthologous system and its high expression in vivo during infection in a murine model of invasive pulmonary aspergillosis (McDonagh et al, 2008). In this present study we demonstrate essentiality of the TrxR-encoding trxR gene for A. fumigatus and describe its characterization by a conditional promoter replacement strategy with respect to oxidative stress resistance, trxR transcription, and virulence, making a case for the sulfur-based redox-active Trx/TrxR system to be recognized as potential antifungal target
Thioredoxin Reductase of Aspergillus fumigatus Is Encoded by the Essential trxR Gene
Summary
Fungi as infectious agents of man pose a constant threat to a specific cohort of individuals, mainly immunosuppressed patients and people living in areas being endemic for primary fungal pathogens (Brown et al, 2012; Köhler et al, 2017). With respect to pathogenicity and the evolution of virulence determinants in the fungal kingdom, several scenarios have been conceived, among them the idea that the primary environmental niche may serve as a training ground and virulence school, resulting in the emergence of specific traits that support fitness, resistance, or invasion during infection (Brunke et al, 2016). This is of special relevance when considering opportunistic fungal pathogens that usually inhabit specific ecological sites in the wild to become only pathogenic when encountered by a susceptible, immunocompromised host. Resistance against oxidative stress has to be considered as a paramount feature of fungal pathogens, which is supported by numerous studies demonstrating that corresponding detoxification systems contribute to the virulence potential of a given fungal pathogen (Brown et al, 2007; Leal et al, 2012; Dantas Ada et al, 2015; Brown and Goldman, 2016; Hillmann et al, 2016; Shlezinger et al, 2017)
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