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Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger , and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing the spliceosome, osteoclast differentiation, and coagulation pathways. Utilizing a specific inhibitor and gene-deficient mice, we demonstrate that STAT6 is required for mycosis-induced sinus inflammation. These findings confirm the relevance of this new model and portend future studies that further extend our understanding of the immunopathologic basis of airway mycosis and unified airway disease., Competing Interests: DC and JK hold intellectual property in PM-43I. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with the author YZ at the time of review., (Copyright © 2022 Sun, Damania, Mair, Otukoya, Li, Polsky, Zeng, Alt, Citardi, Corry, Luong and Knight.)

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses. [Display omitted] • Candida albicans drives Th2 and Th17 responses through candidalysin • Candidalysin signals through platelet-expressed GP1bα to promote Dkk-1 release • Platelet-derived Dkk-1 drives Th2 and Th17 responses and allergic airway disease • Platelet-dependent T cell and hemostatic responses protect against C. albicans Candida albicans causes Th2 and Th17 cell-dependent allergic airway disease, but the pathogenesis is obscure. Wu, et al., reveal an allergic effector pathway in which the C. albicans factor candidalysin signals through platelet-expressed GP1bα to drive release of dickkopf 1 (Dkk-1) that in turn promotes antifungal T cell responses. [ABSTRACT FROM AUTHOR]