title: Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection.
abstract: Respiratory syncytial virus (RSV) infection is the number one cause of bronchiolitis in infants, yet no vaccines are available because of a lack of knowledge of the infant immune system. Using a neonatal mouse model, we previously revealed that mice initially infected with RSV as neonates develop Th2-biased immunopathophysiologies during reinfection, and we demonstrated a role for enhanced interleukin-4 receptor α (IL-4Rα) expression on T helper cells in these responses. Here we show that RSV infection in neonates induced limited type I interferon (IFN) and plasmacytoid dendritic cell (pDC) responses. IFN alpha (IFN-α) treatment or adoptive transfer of adult pDCs capable of inducing IFN-α prior to neonatal RSV infection decreased Th2-biased immunopathogenesis during reinfection. A reduced viral load and downregulation of IL-4Rα on Th2 cells were observed in IFN-α-treated neonatal mice, suggesting dual mechanisms of action.
  
  
  OBJECTIVE
  Respiratory syncytial virus (RSV) is the most significant cause of lower respiratory tract infection in infancy worldwide. Despite the dire need, we have failed to produce efficacious RSV vaccines or therapeutics. Part of the reason for this failure is our lack of understanding of how RSV interacts with the infant immune system to suppress the development of protective immunity. In the study described in the present paper, we used a neonatal mouse model, which more closely mimics human infants, to study the role of the innate immune system, particularly type I interferons (IFNs) and plasmacytoid dendritic cells (pDCs), in the pathogenesis of RSV infection. RSV infection in neonates induced limited type I IFN and pDC responses. IFN-α treatment or adoptive transfer of adult pDCs capable of producing IFN-α prior to neonatal RSV infection decreased Th2-biased immunopathogenesis during reinfection. These data suggest that IFN-α is a promising target for future RSV vaccine design.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Bishwas
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Greg I
authors.initials: GI
authors.lastname: Lee
authors.affiliation: College of Medicine, Hunan Normal University, Changsha, Hunan, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: DeVincenzo
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA dyou@uthsc.edu.
authors.forename: Dahui
authors.initials: D
authors.lastname: You
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014709:Vero Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D019562:Viral Load / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D016898:Interferon-alpha; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit