title: Neonatal rhinovirus infection induces mucous metaplasia and airways hyperresponsiveness.
abstract: Recent studies link early rhinovirus (RV) infections to later asthma development. We hypothesized that neonatal RV infection leads to an IL-13-driven asthma-like phenotype in mice. BALB/c mice were inoculated with RV1B or sham on day 7 of life. Viral RNA persisted in the neonatal lung up to 7 d postinfection. Within this time frame, IFN-α, -β, and -γ peaked 1 d postinfection, whereas IFN-λ levels persisted. Next, we examined mice on day 35 of life, 28 d after initial infection. Compared with sham-treated controls, virus-inoculated mice demonstrated airways hyperresponsiveness. Lungs from RV-infected mice showed increases in several immune cell populations, as well as the percentages of CD4-positive T cells expressing IFN-γ and of NKp46/CD335(+), TCR-β(+) cells expressing IL-13. Periodic acid-Schiff and immunohistochemical staining revealed mucous cell metaplasia and muc5AC expression in RV1B- but not sham-inoculated lungs. Mucous metaplasia was accompanied by induction of gob-5, MUC5AC, MUC5B, and IL-13 mRNA. By comparison, adult mice infected with RV1B showed no change in IL-13 expression, mucus production, or airways responsiveness 28 d postinfection. Intraperitoneal administration of anti-IL-13 neutralizing Ab attenuated RV-induced mucous metaplasia and methacholine responses, and IL-4R null mice failed to show RV-induced mucous metaplasia. Finally, neonatal RV increased the inflammatory response to subsequent allergic sensitization and challenge. We conclude that neonatal RV1B infection leads to persistent airways inflammation, mucous metaplasia, and hyperresponsiveness, which are mediated, at least in part, by IL-13.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109-5688, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneider
authors.forename: Jun Y
authors.initials: JY
authors.lastname: Hong
authors.forename: Antonia P
authors.initials: AP
authors.lastname: Popova
authors.forename: Emily R
authors.initials: ER
authors.lastname: Bowman
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Linn
authors.forename: Alan M
authors.initials: AM
authors.lastname: McLean
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Joanne
authors.initials: J
authors.lastname: Sonstein
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Jason B
authors.initials: JB
authors.lastname: Weinberg
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.forename: Uma S
authors.initials: US
authors.lastname: Sajjan
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D010850:Picornaviridae Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology / Q000821:virology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology*
chemical_list: D016207:Cytokines