title: Role for innate IFNs in determining respiratory syncytial virus immunopathology.
abstract: Respiratory syncytial virus (RSV) is the major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. The difficulties involved in RSV vaccine development were recognized in an early vaccine trial, when children immunized with a formalin-inactivated virus preparation experienced enhanced illness after natural infection. Subsequent research in animal models has shown that the vaccine-enhanced disease is mediated at least in part by memory cells producing Th2 cytokines. Previously we had observed enhanced, eosinophilic lung pathology during primary infection of IFN-deficient STAT1(-/-) mice that are incapable of generating Th1 CD4(+) cells. To determine whether these effects depended only on Th2 cytokine secretion or involved other aspects of IFN signaling, we infected a series of 129SvEv knockout mice lacking the IFN-alphabetaR (IFN-alphabetaR(-/-)), the IFN-gammaR (IFN-gammaR(-/-)), or both receptors (IFN-alphabetagammaR(-/-)). Although both the IFN-gammaR(-/-) and the IFN-alphabetagammaR(-/-) animals generated strong Th2 responses to RSV-F protein epitopes, predominantly eosinophilic lung disease was limited to mice lacking both IFNRs. Although the absolute numbers of eosinophils in BAL fluids were similar between the strains, very few CD8(+) T cells could be detected in lungs of IFN-alphabetagammaR(-/-) animals, leaving eosinophils as the predominant leukocyte. Thus, although CD4(+) Th2 cell differentiation is necessary for the development of allergic-type inflammation after infection and appears to be unaffected by type I IFNs, innate IFNs clearly have an important role in determining the nature and severity of RSV disease.
authors.affiliation: Columbus Children's Research Institute and Department of Pediatrics, Ohio State University College of Medicine and Public Health, Columbus, 43205, USA.
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mertz
authors.forename: Negin
authors.initials: N
authors.lastname: Gitiban
authors.forename: Sue
authors.initials: S
authors.lastname: Hammond
authors.forename: Robin
authors.initials: R
authors.lastname: Legallo
authors.forename: Russell K
authors.initials: RK
authors.lastname: Durbin
authors.forename: Joan E
authors.initials: JE
authors.lastname: Durbin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D007372:Interferons; D008565:Membrane Proteins; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse