FIBCD1 Binds Aspergillus fumigatus and Regulates Lung Epithelial Response to Cell Wall Components

Abstract

Aspergillus fumigatus (A. fumigatus) is a ubiquitous fungus of clinical importance associated with development of various pulmonary diseases and allergic hypersensitivity reactions. It is protected against environmental stress by a cell wall that contains polysaccharides such as chitin. We previously demonstrated that fibrinogen C domain-containing protein 1 (FIBCD1) is a membrane-bound protein that binds chitin through a conserved S1 binding site and is expressed in intestinal epithelium and salivary glands. Here, we further localized FIBCD1 protein expression at the surface of bronchial and alveolar human lung epithelium, observed recognition of A. fumigatus cell wall with S1 site-independent recognition. We observed FIBCD1-mediated suppression of IL-8 secretion, mucin production, and transcription of genes associated with airway inflammation and homeostasis in FIBCD1-transfected lung epithelial cells. These modulations were generally enforced by stimulation with A. fumigatus cell wall polysaccharides. In parallel, we demonstrated a FIBCD1-mediated modulation of IL-8 secretion induced by TLR2,−4, and −5. Collectively, our findings support FIBCD1 as a human lung epithelial pattern recognition receptor that recognizes the complex A. fumigatus cell wall polysaccharides and modulates the lung epithelial inflammatory response by suppressing inflammatory mediators and mucins.

Modulation of the fungal mycobiome is regulated by the chitin-binding receptor FIBCD1

“…Statistics: Data are presented as mean ± SEM where dots represent individual mice. Oneway ANOVA followed by Tukey post hoc test was used to analyze results in A and B, and unpaired Student's t test was used to analyze data in D. **, P < 0.01 and ****, P < 0.0001. epithelial responses at steady state as well as upon stimulation with fungal cell wall components and a variety of TLR agonists (Jepsen et al, 2018). Yet, when sort-purified CD45 − CD326 + IECs from Fibcd1 Tg mice were assessed for the expression of a wide range of genes associated with mucus production (Muc2 and Muc5Ac), cell adhesion/tight junction formation (Cd326, Icam1, Zo1, Cldn1, and Cldn2), immune responses (Ccl2, Ccl20, and Tslp) and production of anti-microbial peptides (Reg3a and Reg3g), no significant differences were observed compared with WT littermates (Fig.…”

“…Since FIBCD1 is a novel receptor of chitin capable of binding chitin-rich regions of A. fumigatus (Jepsen et al, 2018) and recent studies have highlighted the importance of interactions between host and fungi present at barrier surfaces (Iliev et al, 2012;Wheeler et al, 2016;Leonardi et al, 2018), we tested whether IEC-restricted expression of FIBCD1 would influence the composition of the gut mycobiome. Initial characterization by quantitative PCR (qPCR) of the relative abundance of fungal 18S ribosomal DNA in WT and Fibcd1 Tg littermates cohoused in mixed litters did not reveal any significant changes in fungal burden ( Fig.…”

“…FIBCD1, a transmembrane protein tetramer that structurally resembles the ficolin family of pattern recognition receptors, binds chitin and other acetylated structures with high affinity in vitro (Schlosser et al, 2009;Thomsen et al, 2010). Unlike the ficolins, FIBCD1 does not bind to conventional microbe-associated molecular patterns, such as LPS, peptidoglycan, lipoteichoic acid, or β-glucan, yet it appears to bind chitin, recognize chitin-rich regions of Aspergillus fumigatus and modulate cellular responses to fungal cell wall components in a human lung epithelial cell line in vitro (Schlosser et al, 2009;Jepsen et al, 2018).…”

Aspergillus fumigatus and Aspergillosis in 2019

“…Few molecules have been identified to date in the initial interaction between the fungus and the epithelial cells: (i) the fucose lectin FleA, interacting with mucins favors mucociliary clearance (214), (ii) the suface invasin CalA, which interacts with a 5 b 1 integrin (217), (iii) the galactosaminogalactan adhesin binding nonspecifically to the epithelium (218), and (iv) a fibrinogen C domain-containing protein 1 (FIBCD1) binding to chitin (219).…”

How Fungal Glycans Modulate Platelet Activation via Toll-Like Receptors Contributing to the Escape of Candida albicans from the Immune Response

“…Rivera et al showed that FIBCD1 is expressed in epithelial cells of human lung that recognize the fungal cell wall. The sensing of the fungal cell wall by FIBCD1 results in the suppression of epithelial inflammatory signalling, such as IL-8 and mucin production, indicating that FIBCD1 activation has an impact on the modulation of the immune response by decreasing antifungal elimination through the disruption of neutrophil recruitment and mucin production [62]. Wagner et al showed that chitin from C. albicans increases arginase-1 activity in human macrophages and suppresses NO synthesis, suggesting that chitin can influence macrophage function by reducing antimicrobial activities and mediating fungal survival [63].…”