Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

The causes of death from intranasal cowpox virus infections in mice remain unclear. Hypotheses include severe pneumonitis, hepatitis, and/or hyperproduction of cytokines and chemokines. This work explores these hypotheses by studying the influence of low and high volume virus inoculums on viral pathogenesis. BALB/c mice were infected intranasally with a syncytium-forming variant of cowpox virus in 5-μl or 50-μl volumes containing the same infectious virus challenge dose. The 50-μl infection produced a more rapidly lethal disease associated with severe pneumonitis, high lung and nasal virus titers, and increases in cytokine and chemokine levels in lungs and nasal tissue, while liver infection was minimal. The 5-μl inoculum infection was also lethal, but the infection was primarily confined to the upper respiratory tract, and included elevated nasal cytokine and chemokine levels. The pro-inflammatory cytokine, interleukin-6, was particularly high in both infections. Treatment of the infections with cidofovir (100 mg/kg/day for 2 days starting 24 h after virus exposure) led to survival and suppression of tissue virus titers. Treatment reduced pneumonitis in the 50-μl infection, and lessened cytokine hyperproduction in both infections. We conclude that 5-μl volume inoculum of cowpox virus causes a lethal upper respiratory tract infection, while the 50-μl inoculum targets both upper and lower respiratory tracts, with excessive release of systemic pro-inflammatory factors occurring. Cidofovir effectively treated both infections and slowed viral replication sufficiently to subdue the exaggerated release of pro-inflammatory mediators.