Fungi in Mucoobstructive Airway Diseases

Abstract

Asthma, chronic rhinosinusitis, and related incurable allergic afflictions of the upper and lower airways are medically important because of their association with the disabling symptom of dyspnea and, at least for asthma, the potential to cause fatal asphyxiation. Extensive research over the past two decades has uncovered both the physiological basis of airway obstruction in asthma and key governing molecular pathways. Exaggerated airway constriction in response to diverse provocative stimuli, termed airway hyperresponsiveness, is mediated through the cytokines interleukin 4 (IL-4) and IL-13 and the transcription factor signal transducer and activator of transcription 6 (STAT6). Overproduction of mucus has long been known to be an essential second component of airway obstruction and is also mediated in part through the IL-4/IL-13/STAT6 pathway. In this review, we discuss a second major signaling pathway which underlies mucus production that is mediated through proteinase-cleaved fibrinogen signaling through Toll-like receptor 4. Unexpectedly, our analysis of human sputum and paranasal sinus fluid indicates that in most cases of severe allergic airway disease, a unique type of airway fungal infection, termed airway mycosis, is pathogenically linked to these conditions. We further discuss how fungal and endogenous proteinases mediate the fibrinogenolysis that is essential to both Toll-like receptor 4 signaling and fibrin deposition that, together with mucus, contribute to airway obstruction.

Keywords: airway mycosis; asthma; chronic rhinosinusitis; fibrinogen; fungi.

Figure 1.

Environmental and immune factors mediating airway obstruction in asthma. Many inhaled substances, including mites, various pollutants, and proteases, can either induce or exacerbate asthma. These factors enter the airway lumen to trigger innate immune allergic responses by activating pattern recognition receptors (PRRs), including Toll-like receptor 4 (TLR4) and others expressed on airway epithelial cells. Epithelial cells then secrete cytokines such as interleukin 25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) into the subepithelial space to promote the development of innate lymphoid cell type 2 (ILC2) and dendritic cells that migrate to draining lymph nodes and to promote development of T helper type 2 (T_H2) cells and immunoglobulin E (IgE)-secreting B cells. At the same time, inhaled proteinases promote the breakdown of fibrinogen into fibrinogen cleavage products (FCP) that signal through TLR4 to initiate airway hyperreactivity, eosinophilia, and mucus hypersecretion. Proteinases may also interact with protease-activated receptor 2 (PAR2) to either promote or attenuate asthma. With sustained exposure to allergens or establishment of airway mycosis, the low-grade innate allergic inflammation that characterizes healthy lungs converts to an activated lung phenotype characterized by more persistent and intense allergic inflammation. When combined with certain host susceptibility factors, this inflammation evolves further into the asthmatic lung that is dominated by the recruitment and effects of T_H2 cells (via chemokine [C-C motif] ligand 26 [CCL26]) and T_H17 cells, eosinophils (under the direction of IL-5), and mast cells (under the direction of IL-4 and IgE), which promote severe allergic inflammation, airway hyperreactivity, and mucus hypersecretion. APC = antigen-presenting cell. Image courtesy of J. Morgan Knight. Reprinted by permission from Reference .