title: H-ficolin binds Aspergillus fumigatus leading to activation of the lectin complement pathway and modulation of lung epithelial immune responses.
abstract: Aspergillus fumigatus is an opportunistic fungal pathogen that typically infects the lungs of immunocompromised patients leading to a high mortality. H-Ficolin, an innate immune opsonin, is produced by type II alveolar epithelial cells and could participate in lung defences against infections. Here, we used the human type II alveolar epithelial cell line, A549, to determine the involvement of H-ficolin in fungal defence. Additionally, we investigated the presence of H-ficolin in bronchoalveolar lavage fluid from transplant patients during pneumonia. H-Ficolin exhibited demonstrable binding to A. fumigatus conidia via l-fucose, d-mannose and N-acetylglucosamine residues in a calcium- and pH-dependent manner. Moreover, recognition led to lectin complement pathway activation and enhanced fungal association with A549 cells. Following recognition, H-ficolin opsonization manifested an increase in interleukin-8 production from A549 cells, which involved activation of the intracellular signalling pathways mitogen-activated protein kinase MAPK kinase 1/2, p38 MAPK and c-Jun N-terminal kinase. Finally, H-ficolin concentrations were significantly higher in bronchoalveolar lavage fluid of patients with lung infections compared with control subjects (n = 16; P = 0·00726). Receiver operating characteristics curve analysis further highlighted the potential of H-ficolin as a diagnostic marker for lung infection (area under the curve = 0·77; P < 0·0001). Hence, H-ficolin participates in A. fumigatus defence through the activation of the lectin complement pathway, enhanced fungus-host interactions and modulated immune responses.
authors.affiliation: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, UK.|Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bidula
authors.affiliation: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, UK.|School of Pharmacy and Biomolecular Science, Liverpool John Moores University, Liverpool, UK.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Sexton
authors.affiliation: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Yates
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Alireza
authors.initials: A
authors.lastname: Abdolrasouli
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Anand
authors.initials: A
authors.lastname: Shah
authors.affiliation: Departments of Infection, Immunity and Inflammation and Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.affiliation: Department of Lung Transplantation, Harefield Hospital, Middlesex, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Reed
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Darius
authors.initials: D
authors.lastname: Armstrong-James
authors.affiliation: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, UK.|Department of Microbiology, Royal Brompton Hospital, London, UK.
authors.forename: Silke
authors.initials: S
authors.lastname: Schelenz
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D019540:Area Under Curve; D001232:Aspergillus fumigatus / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003167:Complement Activation; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism; D037582:Complement Pathway, Mannose-Binding Lectin; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D037102:Lectins / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D020935:MAP Kinase Signaling System; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011237:Predictive Value of Tests; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D012372:ROC Curve; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C508606:CXCL8 protein, human; C109662:FCN3 protein, human; D006023:Glycoproteins; D016209:Interleukin-8; D037102:Lectins; D003179:Complement C3b
keywords: Aspergillus; complement; ficolin; innate immunity