Aspergillosis and the role of mucins in cystic fibrosis

Abstract

SummaryThe prevalence of aspergillosis in CF patients has until recently been underestimated, but increasing evidence suggests that it may play an important role in the progression of CF lung disease. In healthy airways, Aspergillus fumigatus can be efficiently removed from the lung by mechanisms such as mucociliary clearance and cough. However, these mechanisms are defective in CF, allowing pathogens such as A. fumigatus to germinate and establish chronic infections within the airways. The precise means by which A. fumigatus contributes to CF lung disease remain largely unclear. As the first point of contact within the lung, and an important component of the innate immune system, it is likely that the mucus barrier plays an important role in this process. Study of the functional interplay between this vital protective barrier, and in particular its principal structural components, the polymeric gel‐forming mucins, and CF pathogens such as A. fumigatus, is at an early stage. A. fumigatus protease activity has been shown to upregulate mucus production by inducing mucin mRNA and protein expression, and A. fumigatus proteases and glycosidases are able to degrade mucins. This may allow A. fumigatus to alter mucus barrier properties to promote fungal colonization of the airways and/or utilize mucins as a nutrient source. Moreover, conidial surface lectin binding to mucin glycans is a key aspect of clearance of Aspergillus from the lung in health but may be an important aspect of colonization, where mucociliary clearance is compromised, as in the CF lung. Here we discuss the nature of the mucus barrier and its mucin components in CF, and how they may be implicated in A. fumigatus infection. Pediatr Pulmonol 2017;52:548–555. © 2016 The Authors. Pediatric Pulmonology. Published by Wiley Periodicals, Inc.

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

“…Neutrophil elastase drives multiple aspects of CF lung disease, including increased mucus production and impairment of mucociliary clearance [109]. Both outcomes promote colonization of the airways by opportunistic fungal pathogens such as Aspergillus, which has a complex array of interactions with airway mucins [110]. Considering that this protease is being actively secreted by neutrophils undergoing pathological conditioning in the CF airways [105], with similar dysfunctions observed in other respiratory diseases [111], NE inhibition may offer a therapeutic option for treating pulmonary fungal infections.…”

Aspergillus fumigatus in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis

“…In healthy, immunocompetent hosts, inhaled A. fumigatus spores are eliminated by the mucociliary elevator and alveolar macrophages . The ability of the host's immune system to mount an efficient response is crucial if the first line of defense is overwhelmed.…”

Exposure to mold proteases stimulates mucin production in airway epithelial cells through Ras/Raf1/ERK signal pathway

“…The effects of enhanced mucin gene expression and protein production were likely protective in the acute phase as the mucociliary escalator is one of the most powerful innate defense mechanisms for environmental insults. Interestingly, serine protease secreted by A.fumigatus was shown to degrade airway mucus [62], likely utilizing these degraded polysaccharides and proteinaceous substrates as food sources [63,64] or serving as a counter-measure. However, in the chronic phase, overproduced mucin proteins may obstruct the airway and induce AHR.…”