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

Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-gamma production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown.

Objectives: To define the role of IFN-gamma in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice.

Methods: Wild-type (WT) and IFN-gamma 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-gamma knockout mice developed similar levels of AHR and airway inflammation after primary Infection. After reinfection, IFN-gamma knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-gamma during primary Infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-gamma knockout mice. Adoptive transfer of WT T cells into IFN-gamma knockout mice before primary Infection restored IFN-gamma production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-gamma during primary neonatal Infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection.

Conclusions: IFN-gamma production during primary RSV Infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-gamma during primary Infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.