An IFN-STAT1-CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk During Aspergillus fumigatus Infection
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Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb , which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.
Graphic abstract
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pDC activation in the infected lung coincides with type I and type III interferon production.
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pDCs represent a major, but not exclusive source of type I and type III IFN in the Aspergillus-infected lung.
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These pDC-derived products act on type I and type III IFN receptor + lung neutrophils via STAT1 signal transduction.
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STAT1-dependent neutrophil fungal killing and ROS production is attenuated in the absence of pDCs.
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expression regulates Cybb transcription and CYBB protein levels in neutrophils, but does not regulate the transcription or translation of other subunits of neutrophil NADPH oxidase.
