Altered pathogenesis of severe pneumovirus infection in response to combined antiviral and specific immunomodulatory agents

Abstract

We report here the responses of mice with symptomatic pneumovirus infection to combined antiviral and specific immunomodulatory agents. Mice infected with pneumonia virus of mice, a natural mouse pathogen that replicates the signs and symptoms of severe infection with respiratory syncytial virus (RSV), responded to the antiviral agent ribavirin when it was administered in the setting of endogenous (gene deletion) or exogenous (antibody-mediated) blockade of the MIP-1alpha proinflammatory signaling cascade. Although neither treatment is effective alone, together they offer a dramatic reduction in symptoms and pathology, the most impressive of which is a significant reduction in morbidity and mortality. The findings presented are consistent with the notion of unique and independent contributions of virus replication and ongoing inflammation to the pathogenesis of severe respiratory virus infection, and they provide the impetus for the study of this treatment regimen in RSV-infected humans.

FIG. 1.

Mean clinical scores of wild-type mice infected with PVM strain J3666 on day 0 and treated twice daily by intraperitoneal administration of ribavirin (75 mg/kg/day in two divided doses; open circles) or diluent control (PBS; filled circles) beginning on day 3. Clinical scoring system (10, 13): 1, healthy; 2, ruffled fur at neck; 3, piloerection and difficulty breathing, less alert; 4, lethargic with labored breathing; 5, premorbid with emaciation and cyanosis; 6, death. Error bars indicate the standard error of the mean. No statistically significant differences were observed.

FIG. 2.

Mean clinical scores of MIP-1α^−/− mice infected with PVM on day 0 and treated intraperitoneally with ribavirin (75 mg/kg/day administered in two divided doses; open squares) or diluent control (filled squares) beginning on day 3. The clinical scoring system used and the error bars are described in the legend to Fig. 1. P < 0.001 at the time points indicated.

FIG. 3.

Survival analysis of wild-type (MIP-1α^+/+; all circles) and gene deletion-containing (MIP-1α^−/−; all squares) mice inoculated with 60 PFU of PVM on day 0 and treated with ribavirin (75 mg/kg/day administered in two divided doses; filled symbols) or diluent control (open symbols) beginning on day 3 (10 mice per group). Significantly improved survival of ribavirin-treated MIP-1α^−/− mice, compared independently with that of each of the other three groups (P < 0.001), was observed.

FIG. 4.

Survival analysis of wild-type mice inoculated with 60 PFU of PVM on day 0 and treated with ribavirin (75 mg/kg/day administered in two divided doses; filled symbols) or diluent control (open symbols) and goat anti-mMIP-1α (5 μg/day administered intraperitoneally; squares) or goat isotype control (same dose; circles) beginning on day 3 (10 mice per group). Significantly improved survival of combined ribavirin- and anti-mMIP-1α-treated mice, compared independently to that of each of the other three groups (P < 0.001), was observed.