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

Abstract

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 proinflammatory factors occurring. Cidofovir effectively treated both infections and slowed viral replication sufficiently to subdue the exaggerated release of pro-inflammatory mediators.

Clinical Course and Pathology in Rats (Rattus norvegicus) After Experimental Cowpox Virus Infection by Percutaneous and Intranasal Application

“…12 Even the volume of the virus inoculum has an influence on the pathogenesis, as shown in BALB/c mice with a syncytium-forming variant of cowpox virus: a high-volume infection produced a more rapid lethal disease associated with severe pneumonia, whereas a lowvolume infection remained primarily confined to the upper respiratory tract. 20 Factors such as immunosuppression can influence the course of CPXV infection. Immunosuppressive diseases-for example, in cats-caused by concurrent infection with feline immunodeficiency virus (FIV) or feline leukemia virus (FeLV) have also led to fatal complications during cowpox virus infection.…”

KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo

“…In contrast, oral administration of 4=-thioIDU (15 mg/kg twice daily for 5 consecutive days beginning at 24 h after infection) reduced lung virus titers by only 10-fold, as reported by Kern and colleagues (27), although differences in the doses and routes of administration of the compounds and/or the volume of virus inoculated might be at the origin of the discrepancy in the results. Histology of the lungs of VACV-WR-infected mice revealed signs only of inflammation and not of pneumonia, which could be due to (i) the time point of sacrifice of the animals, i.e., at day 5 p.i., or (ii) the use of a relatively small volume for virus inoculation, as discussed by Smee and colleagues (48).…”

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

“…204 In recent years, the activity of cidofovir has been further documented against rabbitpox virus in rabbits, 205 mousepox in mice, 206 monkeypox in mice, 207 cowpox in mice 208 [the zoonotic cowpox virus is considered an emerging health threat 209 ] and Cantagalo virus in vitro 210 [Cantagalo virus has been isolated during an outbreak of a pustular disease in dairy farms in Brazil; it may derive from the Brazilian smallpox vaccine 211 ]. Cidofovir has also proven strongly inhibitory to parapoxviruses in vitro, 212 including the orf virus 213,214 and the sea lion poxvirus.…”