Necessary and Sufficient Role for T Helper Cells To Prevent Fungal Dissemination in Allergic Lung Disease

Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections with Curvularia lunata and Aspergillus fumigatus were typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia of Aspergillus fumigatus administered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient MT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination. The pathogenic filamentous fungi comprise numerous sporulating, saprophytic organisms that may be significant causes of human disease under select circumstances. The most common of these potential pathogens derive from relatively few genera, including Aspergillus, Penicillium, Curvularia, Coccidioides, and others. Fungus-related determinants of pathogenicity are not fully understood but include proximity to human work and living spaces, ease of entry into the body, most often involving inhalation of spore-containing aerosols, and production of a variety of virulence factors that allow adherence to and invasion of host cells, competition for limiting nutrients, and resistance against sophisticated host immune responses (58). Filamentous fungi are linked to multiple disease syndromes involving the airways. In addition to asymptomatic colonization of the upper and lower respiratory tracts, fungi are strongly linked to noninvasive disease processes in which organism growth is confined to the airway epithelial surface in association with allergic fungal rhinosinusitis (AFRS) (33), allergic bronchopulmonary aspergillosis (ABPA) (48), and aspergillomas (fungus balls). Additional syndromes in which fungi become locally invasive in the airway epithelium and submucosa,