title: Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells.
abstract: BACKGROUND
  Early-life human rhinovirus infection has been linked to asthma development in high-risk infants and children. Nevertheless, the role of rhinovirus infection in the initiation of asthma remains unclear.
  
  
  OBJECTIVE
  We hypothesized that, in contrast to infection of mature BALB/c mice, neonatal infection with rhinovirus promotes an IL-25-driven type 2 response, which causes persistent mucous metaplasia and airways hyperresponsiveness.
  
  
  METHODS
  Six-day-old and 8-week-old BALB/c mice were inoculated with sham HeLa cell lysate or rhinovirus. Airway responses from 1 to 28 days after infection were assessed by using quantitative PCR, ELISA, histology, immunofluorescence microscopy, flow cytometry, and methacholine responsiveness. Selected mice were treated with a neutralizing antibody to IL-25.
  
  
  RESULTS
  Compared with mature mice, rhinovirus infection in neonatal mice increased lung IL-13 and IL-25 production, whereas IFN-γ, IL-12p40, and TNF-α expression was suppressed. In addition, the population of IL-13-secreting type 2 innate lymphoid cells (ILC2s) was expanded with rhinovirus infection in neonatal but not mature mice. ILC2s were the major cell type secreting IL-13 in neonates. Finally, anti-IL-25 neutralizing antibody attenuated ILC2 expansion, mucous hypersecretion, and airways responsiveness.
  
  
  CONCLUSIONS
  These findings suggest that early-life viral infection could contribute to asthma development by provoking age-dependent, IL-25-driven type 2 immune responses.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Yutein
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Steenrod
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Uma S
authors.initials: US
authors.lastname: Sajjan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich. Electronic address: mhershen@umich.edu.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D049109:Cell Proliferation; D002648:Child; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009093:Mucus / Q000276:immunology; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000276:immunology* / Q000473:pathology; D012229:Rhinovirus / Q000276:immunology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D007378:Interleukins; C442281:Mydgf protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Asthma; IL-25; mouse; neonatal; rhinovirus; type 2 innate lymphoid cells