title: Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation.
abstract: ATP-binding cassette transporter A3 (ABCA3) is a lipid transporter active in lung alveolar epithelial type II cells (ATII) and is essential for their function as surfactant-producing cells. ABCA3 mutational defects cause respiratory distress in newborns and interstitial lung disease (ILD) in children. The molecular pathomechanisms are largely unknown; however, viral infections may initiate or aggravate ILDs. Here, we investigated the impact of the clinically relevant ABCA3 mutations, p.Q215K and p.E292V, by stable transfection of A549 lung epithelial cells. ABCA3 mutations strongly impaired expression of the ATII differentiation marker SP-C and the key epithelial cell adhesion proteins E-cadherin and zonula occludens-1. Concurrently, cells expressing ABCA3 mutation acquired mesenchymal features as observed by increased expression of SNAI1, MMP-2 and TGF-β1, and elevated phosphorylation of Src. Infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children, potentiated the observed mutational effects on loss of epithelial and acquisition of mesenchymal characteristics. In addition, RSV infection of cells harboring ABCA3 mutations resulted in a morphologic shift to a mesenchymal phenotype. We conclude that ABCA3 mutations, potentiated by RSV infection, induce loss of epithelial cell differentiation in ATII. Loss of key epithelial features may disturb the integrity of the alveolar epithelium, thereby comprising its functionality. We suggest the impairment of epithelial function as a mechanism by which ABCA3 mutations cause ILD.
authors.affiliation: German Center for Lung Research, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kaltenborn
authors.forename: Suncana
authors.initials: S
authors.lastname: Kern
authors.forename: Sabrina
authors.initials: S
authors.lastname: Frixel
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fragnet
authors.forename: Karl-Klaus
authors.initials: KK
authors.lastname: Conzelmann
authors.forename: Ralf
authors.initials: R
authors.lastname: Zarbock
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D017563:Lung Diseases, Interstitial / Q000235:genetics / Q000821:virology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology / Q000821:virology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C569042:TJP1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D062826:Zonula Occludens-1 Protein; D020778:Matrix Metalloproteinase 2