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

Abstract

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.

Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

“…Airway Hyper-responsiveness Measurement-Measurements of airway hyper-responsiveness were conducted 24 h after the last intra-tracheal challenge with ovalbumin as previously described, with some modifications (28,29). Briefly, rats were anesthetized with etomidate and intubated for continuous ventilation inside a whole body plethysmograph using 100% oxygen to maintain physiologic pH and arterial PCO 2 .…”

Airway surface mycosis in chronic TH2-associated airway disease

“…Prior studies from our laboratories have established that fungal sensitization in CRS is very common and that fungal growth within the airways is essential to the pathophysiology of experimental fungal allergic airway disease in mice 13-15 . We have further shown that fungal proteinases are intimately linked to both anti-fungal immunity and the expression of experimental asthma through the activation of fibrinogen and TLR4 16 .…”

Host Response to Pulmonary Fungal Infections: a Highlight on Cell-Driven Immunity to Cryptococcus Species and Aspergillus fumigatus

“…However, PU.1, a transcriptional regulator of alternative polarization of macrophages, has been implicated in the pathological outcome of Aspergillus -induced asthmatic airway inflammation [38, 39]. Moreover, classical macrophages are a potent source of reactive oxygen species and can promote Th1 response [40, 41], both of which have been shown by our studies and others to be helpful in the control of Aspergillus infection [42–48]. However, as it is becoming more apparent that the distinctions between “classical” and “alternative” are fluid characterizations, it is likely that both macrophage activation states are functionally required for mounting a robust defense against Aspergillus .…”