Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Abstract

Intranasal infection of BALB/c mice with respiratory syncytial virus (RSV)-A2 (0.5 x 10(8) - 2.0 x 10(8) plaque-forming units, PFU) produced disease characterized by weight loss (2-3 g) and mortality (60%-100%) with the mean day of death ranging from 6-7 d after infection. The extent of RSV disease was inoculum titer-dependent and required a replication competent virus. Lung titers of virus peaked at 0.5-1 x 10(6) PFU/g wet weight. Bronchoalveolar lavage fluid (BALF) levels of IL-1beta, TNF-alpha, INF-gamma IL-12, IL-6, MIP-1alpha, RANTES, and protein were elevated, whereas IL-2, IL-4, IL-5, IL-13, and IL-10 were unchanged. Histological assessment of lungs revealed marked inflammatory pathology characterized by bronchiolitis, vasculitis, and interstitial pneumonia. Whole-body plethysmography revealed significant disease-associated deficits of respiratory function. Therapy with ribavirin administered either by the intranasal, subcutaneous, or oral route significantly reduced disease in a dose-dependent manner. Delaying the initiation of therapy resulted in a loss of activity for ribavirin. Synagis administered either intramuscularly as a single dose in prophylaxis or intranasally in prophylaxis, followed by therapy, also significantly reduced disease in a dose-dependent manner. Infection of mice with a high titer inoculum of RSV-A2 resulted in severe and fatal pulmonary disease that was responsive to treatment. This model may be useful to characterize the in vivo activity of experimental therapies for RSV infection.