Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy.
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.
Bolger
Gordon
G
Department of Biological Sciences, Boehringer Ingelheim (Canada) Limited, Research and Development, Laval, Canada. gbolger@lav.boehringer-ingelheim.com
Lapeyre
Nicole
N
Dansereau
Nathalie
N
Lagacé
Lisette
L
Berry
Gerald
G
Klosowski
Katy
K
Mewhort
Tracy
T
Liuzzi
Michel
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D008168:Lung / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D000069455:Palivizumab; D012129:Respiratory Function Tests; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000472:pathogenicity* / Q000502:physiology; D012254:Ribavirin / Q000627:therapeutic use; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D016207:Cytokines; D014764:Viral Proteins; D012254:Ribavirin; D000069455:Palivizumab