IFN-γ production during initial infection determines the outcome of reinfection with respiratory syncytial virus

Young Mok Lee, Nobuaki Miyahara, Katsuyuki Takeda, John Prpich, Anita Oh, Annette Balhorn, Anthony Joetham, Erwin W. Gelfand, Azzeddine Dakhama

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-γ production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown. Objectives: To define the role of IFN-γ in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice. Methods: Wild-type (WT) and IFN-γ knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection. Measurements and Main Results: Both WT and IFN-γ knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-γ knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-γ during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-γ knockout mice. Adoptive transfer of WT T cells into IFN-γ knockout mice before primary infection restored IFN-γ production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-γ during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection. Conclusions: IFN-γ production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-γ during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.

Original languageEnglish
Pages (from-to)208-218
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume177
Issue number2
DOIs
Publication statusPublished - Jan 15 2008

Keywords

  • Airway hyperresponsiveness
  • Asthma
  • Interferon-γ
  • Mice
  • Respiratory syncytial virus

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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