title: Interaction of adenovirus type 5 fiber with the coxsackievirus and adenovirus receptor activates inflammatory response in human respiratory cells.
abstract: The innate immune response to adenovirus (Ad)-derived gene transfer vectors has been shown to initiate immediately after interaction of Ad with respiratory epithelial cells, through the induction of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and JNK mitogen-activated protein kinase (MAPK), nuclear factor kappaB (NF-kappaB), and different proinflammatory genes. Ad serotypes 2 or 5 (Ad2/5) enter respiratory epithelia after initial binding of fiber with the coxsackievirus-adenovirus receptor (CAR) or, alternatively, with cell surface heparan sulfate glycosaminoglycans. Ad2/5 internalization is triggered by binding of penton base to cellular RGD-binding integrins. Here we investigated the role of the Ad5 surface domain proteins constituting the vector capsid, namely, the fiber, the penton base, and the hexon, on the transmembrane signals leading to the transcription of the different proinflammatory genes in the human respiratory A549 cell line. Interaction of Ad fiber with CAR activates both ERK1/2 and JNK MAPK and the nuclear translocation of NF-kappaB, whereas no activation was observed after exposing A549 cells to penton base and hexon proteins. Moreover, interaction of Ad fiber with CAR, but not heparan sulfate proteoglycans, promotes transcription of the chemokines interleukin-8, GRO-alpha, GRO-gamma, RANTES, and interferon-inducible protein 10. These results identify the binding of Ad5 fiber with the cellular CAR as a key proinflammatory activation event in epithelial respiratory cells that is independent of the transcription of Ad5 genes.
authors.affiliation: Laboratorio Patologia Molecolare, Centro Fibrosi Cistica, Azienda Ospedaliera-Universitaria, Piazzale Stefani 1, 37126 Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tamanini
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolis
authors.forename: Alberto
authors.initials: A
authors.lastname: Bonizzato
authors.forename: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.forename: Paola
authors.initials: P
authors.lastname: Melotti
authors.forename: Baroukh M
authors.initials: BM
authors.lastname: Assael
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
mesh_terms: D000260:Adenoviruses, Human / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D036022:Capsid Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D018946:Chemokine CCL5 / Q000235:genetics; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003593:Cytoplasm / Q000737:chemistry; D004847:Epithelial Cells / Q000821:virology*; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011991:Receptors, Virus / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000821:virology*; D014158:Transcription, Genetic
chemical_list: C568771:CLMP protein, human; C475829:CXCL1 protein, human; D036022:Capsid Proteins; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D011991:Receptors, Virus; C018315:hexon capsid protein, Adenovirus; C043322:penton protein, adenovirus; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3