Abstract
Filamentous fungi of the Aspergillus genus and others have long been linked to the induction of type 2 immunity that underlies IgE-mediated hypersensitivity responses. This unique immune response is characterized by the production of the allergy-associated T helper cell type 2 (Th2) and Th17 cytokines interleukin 4 (IL-4), IL-13, and IL-17 that drive IgE, eosinophilia, airway hyperresponsiveness and other manifestations of asthma. Proteinases secreted by filamentous fungi promote type 2 immunity, but the mechanism by which this occurs has long remained obscure. Through detailed biochemical analysis of household dust, microbiological dissection of human airway secretions, and extensive modeling in mice, our laboratory has assembled a detailed mechanistic description of how type 2 immunity evolves after exposure to fungi. In this review we summarize three key discoveries: (1) fungal proteinases drive the type 2 immune response; (2) the relationship between fungi, proteinases, and type 2 immunity is explained by airway mycosis, a form of non-invasive fungal infection of the airway lumen; and (3) the innate component of proteinase-driven type 2 immunity is mediated by cleavage of the clotting protein fibrinogen. Despite these advances, additional work is required to understand how Th2 and Th17 responses evolve and the role that non-filamentous fungi potentially play in allergic diseases.
Highlights
Filamentous fungi, especially Aspergillus spp., are most often acquired by inhalation of conidia.the most common aspergillus-related diseases affect the upper and lower airways. the majority of research in aspergillus-related disease focuses on the highly lethal invasive syndromes involving dissemination of the fungus to other organs, the vast majority of aspergillus-related disease is non-invasive, with the organism remaining confined to the epithelial surface
Should fungi gain a foothold within the airway lumen and begin producing proteinases. These enzymes cleave fibrinogen into fibrinogen cleavage products (FCP) that bind to the integrin Mac-1 and Toll like receptor 4 (TLR4) to activate innate antifungal immunity through macrophages and epithelial cells
Despite the explanatory power of the newly discovered FCP-TLR4 pathway in defining the molecular basis of type 2 immunity and allergic airway disease, we still do not know how Th2 and Th17 cells arise in the context of airway mycosis, we do know that fungal proteinases strongly drive these responses
Summary
John Morgan Knight 1,2 , Yifan Wu 1 , Kelsey Mauk 1 , Jill Weatherhead 3,4 , Sara Anvari 3 , Farrah Kheradmand 1,2,4,5 and David B. Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA
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