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


OBJECTIVE
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.


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.
Lee
Young-Mok
YM
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Miyahara
Nobuaki
N
Takeda
Katsuyuki
K
Prpich
John
J
Oh
Anita
A
Balhorn
Annette
A
Joetham
Anthony
A
Gelfand
Erwin W
EW
Dakhama
Azzeddine
A
D000818:Animals; D000831:Animals, Newborn; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D012008:Recurrence; D018357:Respiratory Syncytial Virus Infections / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load
D007371:Interferon-gamma