title: The respiratory syncytial virus fusion protein and neutrophils mediate the airway mucin response to pathogenic respiratory syncytial virus infection.
abstract: Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater airway necrosis, and higher levels of interleukin-13 (IL-13) and airway mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro, the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2-2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2-2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary mucin expression than infection with the A2 strain. A2-2-20F infection induced greater necrotic airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2-2-20F infection is involved in mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less airway mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in airway epithelium infection, pathogenesis, and subsequent airway mucin expression.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Stokes
authors.forename: Michael G
authors.initials: MG
authors.lastname: Currier
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007223:Infant; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity*; D014759:Viral Envelope Proteins / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000276:immunology / Q000378:metabolism*; D019562:Viral Load
chemical_list: C526850:F protein, human respiratory syncytial virus; D009077:Mucins; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; C116204:attachment protein G