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Dissecting innate immunity to airborne opportunistic fungi through a genome-wide screen in Drosophila

Ziel

In recent years, airborne filamentous fungi have become major causes of life-threatening infections in an expanding population of severely immunocompromised individuals. Aspergillus remains the most common fungal pathogen in these patients, whereas Zygomycetes are emerging causes of fatal invasive fungal infections in many cancer institutions. Overall, the increasing frequency and spectrum of invasive fungal infections and the alarming rates of resistance to antifungal agents in fungi underscores the need to expand our knowledge on the immunopathogenesis of opportunistic fungal infections and develop novel therapeutic strategies. Importantly, the versatility of virulence mechanisms of fungi and the complexity of host defense mechanisms against fungi highlights the importance of understanding the molecular aspects of host-fungal interplay in robust experimental systems.
Over the past decade, invertebrate mini-host models with well-characterized genetics and less complex immunity have been effectively used to explore several aspects of both fungal pathogenicity and antifungal host defense. These properties coupled with the robust genetics in Drosophila, make flies an ideal model to study the molecular aspects of host-fungal interaction.
We have recently implemented Drosophila melanogaster as a model to study virulence mechanisms and the molecular aspects of host immune response to Zygomycetes. Surprisingly, we found that key aspects of the pathophysiology of zygomycosis in humans were appropriately modeled in fruit flies.
In this proposal we expand on our previous work to:
(a) Identify novel genes involved in Drosophila immunity against the most important airborne opportunistic fungi, Aspergillus and Zygomycetes, by performing a genome-wide screening strategy in Drosophila RNAi lines.
(b) Confirm in humans the functional role of novel Drosophila host defense genes by silencing the relevant homologues in human phagocytic cells

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