title: Host proteome correlates of vaccine-mediated enhanced disease in a mouse model of respiratory syncytial virus infection.
abstract: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants. Despite over 50 years of research, to date no safe and efficacious RSV vaccine has been licensed. Many experimental vaccination strategies failed to induce balanced T-helper (Th) responses and were associated with adverse effects such as hypersensitivity and immunopathology upon challenge. In this study, we explored the well-established recombinant vaccinia virus (rVV) RSV-F/RSV-G vaccination-challenge mouse model to study phenotypically distinct vaccine-mediated host immune responses at the proteome level. In this model, rVV-G priming and not rVV-F priming results in the induction of Th2 skewed host responses upon RSV challenge. Mass spectrometry-based spectral count comparisons enabled us to identify seven host proteins for which expression in lung tissue is associated with an aberrant Th2 skewed response characterized by the influx of eosinophils and neutrophils. These proteins are involved in processes related to the direct influx of eosinophils (eosinophil peroxidase [Epx]) and to chemotaxis and extravasation processes (Chil3 [chitinase-like-protein 3]) as well as to eosinophil and neutrophil homing signals to the lung (Itgam). In addition, the increased levels of Arg1 and Chil3 proteins point to a functional and regulatory role for alternatively activated macrophages and type 2 innate lymphoid cells in Th2 cytokine-driven RSV vaccine-mediated enhanced disease.
  
  
  OBJECTIVE
  RSV alone is responsible for 80% of acute bronchiolitis cases in infants worldwide and causes substantial mortality in developing countries. Clinical trials performed with formalin-inactivated RSV vaccine preparations in the 1960s failed to induce protection upon natural RSV infection and even predisposed patients for enhanced disease. Despite the clinical need, to date no safe and efficacious RSV vaccine has been licensed. Since RSV vaccines have a tendency to prime for unbalanced responses associated with an exuberant influx of inflammatory cells and enhanced disease, detailed characterization of primed host responses has become a crucial element in RSV vaccine research. We investigated the lung proteome of mice challenged with RSV upon priming with vaccine preparations known to induce phenotypically distinct host responses. Seven host proteins whose expression levels are associated with vaccine-mediated enhanced disease have been identified. The identified protein biomarkers support the development as well as detailed evaluation of next-generation RSV vaccines.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: van Diepen
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: H Kim
authors.initials: HK
authors.lastname: Brand
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands Viroclinics Biosciences B.V., Rotterdam, The Netherlands.
authors.forename: Leon
authors.initials: L
authors.lastname: de Waal
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Bijl
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Jong
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: Kuiken
authors.affiliation: Viroclinics Biosciences B.V., Rotterdam, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: van Amerongen
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: van den Ham
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marinus J
authors.initials: MJ
authors.lastname: Eijkemans
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands a.andeweg@erasmusmc.nl.
authors.forename: Arno C
authors.initials: AC
authors.lastname: Andeweg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D005260:Female; D008168:Lung / Q000473:pathology; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D020543:Proteome / Q000032:analysis*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D022261:Respiratory Syncytial Virus Vaccines / Q000009:adverse effects* / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D015415:Biomarkers; D020543:Proteome; D022261:Respiratory Syncytial Virus Vaccines