Figures
- Figure 1.
Host–pathogen interactions in cystic fibrosis (CF). This figure illustrates a few of the various interactions between bacterial, viral and fungal pathogens and the CF host. a) Chronically infecting strains of Pseudomonas aeruginosa frequently acquire hypermutable phenotypes through mismatch repair deficiency, encouraging antibiotic resistance and adapted virulence. Inflammatory responses are modulated through changes in lipid A structure and flagellin expression. This provides resistance to host antimicrobial peptides (AMP) and alters CXCL8 production through Toll-like receptor (TLR)4. Loss of motility/changes in flagellin expression can occur in order to evade recognition by TLR5 and phagocytosis by alveolar macrophages. The presence of flagellin can also induce development of myeloid-derived suppressor cells (MDSCs) leading to suppression of T-cell responses. b) Rhinoviral infection may increase expression of cellular adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), and enhance attachment of bacterial pathogens to host cells. c) Decreased uptake of Aspergillus fumigatus conidia by cystic fibrosis transmembrane conductance regulator (CFTR)-deficient epithelial cells results in reduced clearance and increased cell death. Germination from spore to hyphal form results in increased inflammatory responses. Bronchial epithelial cells induce T-cell-mediated T-helper cell (Th)2 and Th17 responses complicit in allergic bronchopulmonary aspergillosis. This may be further enhanced by A. fumigatus mediated downregulation of the vitamin D receptor (VDR) and increased interleukin (IL)-5/IL-13 production by gliotoxin.
Tables
- Table 1. Summary of factors contributing to infection and pulmonary decline in cystic fibrosis
Lung environment Defective cilia function Increased mucus viscosity, hypoxia Free nutrients: amino acids, iron Damage to lung architecture: TGF-β, matrix metalloproteases, neutrophil elastase, oxidant/antioxidant imbalance Altered pH Immune dysfunction Defective and/or decreased antimicrobials: lysozyme, lactoferrin, β-defensins, pentraxin-3, thiocyanate, nitric oxide, surfactant protein D Th2 and Th17 responses Ineffective cellular mediators: neutrophil accumulation and dysfunction Microbial factors Changes in virulence: lipid A structure, flagellin expression, loss of quorum sensing, acquisition of a persistent phenotype and hypermutation Biofilm formation Polymicrobial interaction and secondary infection Direct downregulation of antimicrobial pathways: vitamin D receptor downregulation by Aspergillus TGF: transforming growth factor; Th: T-helper cell.
