Aspergillus fumigatustranscription factor ZfpA regulates hyphal development and alters susceptibility to antifungals and neutrophil killing during infection

Abstract

AbstractHyphal growth is essential for host colonization duringAspergillusinfection. The transcription factor ZfpA regulatesA. fumigatushyphal development including branching, septation, and cell wall composition. However, how ZfpA affects fungal growth and susceptibility to host immunity during infection has not been investigated. Here, we use the larval zebrafish-Aspergillusinfection model and primary human neutrophils to probe how ZfpA affectsA. fumigatuspathogenesis and response to antifungal drugsin vivo. ZfpA deletion promotes fungal clearance and attenuates virulence in wild-type hosts and this virulence defect is abrogated in neutrophil-deficient zebrafish. ZfpA deletion also increases susceptibility to human neutrophilsex vivowhile overexpression impairs fungal killing. Overexpression of ZfpA confers protection against the antifungal caspofungin by increasing chitin synthesis during hyphal development, while ZfpA deletion reduces cell wall chitin and increases caspofungin susceptibility in neutrophil-deficient zebrafish. These findings suggest a protective role for ZfpA activity in resistance to the innate immune response and antifungal treatment duringA. fumigatusinfection.Author SummaryAspergillus fumigatusis a common environmental fungus that can infect immunocompromised people and cause a life-threatening disease called invasive aspergillosis. An important step during infection is the development ofA. fumigatusfilaments known as hyphae.A. fumigatususes hyphae to acquire nutrients and invade host tissues, leading to tissue damage and disseminated infection. In this study we report that a regulator of gene transcription inA. fumigatuscalled ZfpA is important for hyphal growth during infection. We find that ZfpA activity protects the fungus from being killed by innate immune cells and decreases the efficacy of antifungal drugs during infection by regulating construction of the cell wall, an important protective layer for fungal pathogens. Our study introduces ZfpA as an important genetic regulator of stress tolerance during infection that protectsA. fumigatusfrom the host immune response and antifungal drugs.