title: 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.
authors.affiliation: Department of Biological Sciences, Boehringer Ingelheim (Canada) Limited, Research and Development, Laval, Canada. gbolger@lav.boehringer-ingelheim.com
authors.forename: Gordon
authors.initials: G
authors.lastname: Bolger
authors.forename: Nicole
authors.initials: N
authors.lastname: Lapeyre
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dansereau
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacé
authors.forename: Gerald
authors.initials: G
authors.lastname: Berry
authors.forename: Katy
authors.initials: K
authors.lastname: Klosowski
authors.forename: Tracy
authors.initials: T
authors.lastname: Mewhort
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D016207:Cytokines; D014764:Viral Proteins; D012254:Ribavirin; D000069455:Palivizumab