Drosophila melanogaster as a Model Organism for Invasive Aspergillosis
Mammalian hosts have traditionally been considered the “gold standard” models for studying pathogenesis and antifungal drug activity in invasive aspergillosis (IA). Nevertheless, logistical, economical, and ethical constraints make these host systems diff
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Introduction Invasive aspergillosis (IA) is the leading cause of infectious death in patients with leukemia and in recipients of allogeneic hematopoietic stem cell transplantation (1, 2). Although significant advances have occurred over the past decade in antifungal treatment, patients who develop IA still have unfavorable prognoses, reflecting their significant net state of immunosuppression and the suboptimal in vivo efficacy of modern antifungals (1, 2). Thus, new antifungal drug development and introduction of novel therapeutic strategies are important directions in Aspergillus research (3).
Alexandra C. Brand and Donna M. MacCallum (eds.), Host-Fungus Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 845, DOI 10.1007/978-1-61779-539-8_32, © Springer Science+Business Media, LLC 2012
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M.S. Lionakis and D.P. Kontoyiannis
Since the early 2000s, new antifungal drugs with promising in vitro anti-Aspergillus activity have been added to our armamentarium against IA: the new-generation broad-spectrum triazoles and the echinocandins. Because in vitro susceptibility testing of antifungals alone or in different combinations does not reliably correlate with in vivo clinical efficacy (4, 5), evaluation of antifungal activity relies on IA animal model studies, typically using immunocompetent or immunosuppressed mammals, such as rodents, rabbits, and guinea pigs (6–9). Use of these conventional host systems is costly, time consuming, and poses ethical controversies, especially when it comes to testing various antifungal combinations that requires large number of animals. Not surprisingly, use of these animal models is typically limited to testing only one Aspergillus isolate in a small number of animals. The recent completion of the Aspergillus fumigatus genome sequencing project (10), along with significant strides in fungal genetics, has led to a surge of genetic information pertaining to the contribution of individual genes to Aspergillus virulence. For instance, Aspergillus strains with defects in siderophore biosynthesis (DsidA, DsidC, DsidD, DsidF) (11, 12), melanin (Dalb1) (13) or gliotoxin production (DgliP) (14), PABA metabolism (H515) (15), thermotolerance (DcgrA) (16), ras signaling (DrhbA) (17), or starvation stress response (DcpcA) (18) have been shown to be hypovirulent in mammalian models of IA. Several other molecular factors that may be required for an Aspergillus strain to be an effective pathogen are likely to be discovered in the near future. This explosion in functional genomics creates the need for high-throughput screening strategies capable of determining the role of individual Aspergillus genes in virulence. Because studying the pathogenesis of IA in conventional mammalian models is labor intensive, expensive, and has logistical limitations, these hosts present a significant “bottleneck” in large-scale screening of putative Aspergillus mutants. Because of these limitations, several studies of pathogenesis in Aspergillus fumigatus and a variety of other fungal and non-
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