title: Distinct innate immune phagocyte responses to Aspergillus fumigatus conidia and hyphae in zebrafish larvae.
abstract: Aspergillus fumigatus is the most common filamentous fungal pathogen of immunocompromised hosts, resulting in invasive aspergillosis (IA) and high mortality rates. Innate immunity is known to be the predominant host defense against A. fumigatus; however, innate phagocyte responses to A. fumigatus in an intact host and their contributions to host survival remain unclear. Here, we describe a larval zebrafish A. fumigatus infection model amenable to real-time imaging of host-fungal interactions in live animals. Following infection with A. fumigatus, innate phagocyte populations exhibit clear preferences for different fungal morphologies: macrophages rapidly phagocytose conidia and form aggregates around hyphae, while the neutrophil response is dependent upon the presence of hyphae. Depletion of macrophages rendered host larvae susceptible to invasive disease. Moreover, a zebrafish model of human leukocyte adhesion deficiency with impaired neutrophil function also resulted in invasive disease and impaired host survival. In contrast, macrophage-deficient but not neutrophil-deficient larvae exhibited attenuated disease following challenge with a less virulent (ΔlaeA) strain of A. fumigatus, which has defects in secondary metabolite production. Taking these results together, we have established a new vertebrate model for studying innate immune responses to A. fumigatus that reveals distinct roles for neutrophils and macrophages in mediating host defense against IA.
authors.affiliation: Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Knox
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Laboratory of Genetics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Rood
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA npkeller@wisc.edu huttenlocher@wisc.edu.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA npkeller@wisc.edu huttenlocher@wisc.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Huttenlocher
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity; D006790:Host-Parasite Interactions / Q000276:immunology*; D006801:Humans; D025301:Hyphae / Q000276:immunology / Q000472:pathogenicity; D007113:Immunity, Innate; D007814:Larva / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology; D010586:Phagocytes / Q000276:immunology*; D010587:Phagocytosis; D013172:Spores, Fungal / Q000276:immunology / Q000472:pathogenicity; D015027:Zebrafish / Q000276:immunology* / Q000382:microbiology