Use of the Aerosol Rabbitpox Virus Model for Evaluation of Anti-Poxvirus Agents

Abstract

Smallpox is an acute disease caused by infection with variola virus that has had historic effects on the human population due to its virulence and infectivity. Because variola remains a threat to humans, the discovery and development of novel pox therapeutics and vaccines has been an area of intense focus. As variola is a uniquely human virus lacking a robust animal model, the development of rational therapeutic or vaccine approaches for variola requires the use of model systems that reflect the clinical aspects of human infection. Many laboratory animal models of poxviral disease have been developed over the years to study host response and to evaluate new therapeutics and vaccines for the treatment or prevention of human smallpox. Rabbitpox (rabbitpox virus infection in rabbits) is a severe and often lethal infection that has been identified as an ideal disease model for the study of poxviruses in a non-rodent species. The aerosol infection model (aerosolized rabbitpox infection) embodies many of the desired aspects of the disease syndrome that involves the respiratory system and thus may serve as an appropriate model for evaluation of antivirals under development for the therapeutic treatment of human smallpox. In this review we summarize the aerosol model of rabbitpox, discuss the development efforts that have thus far used this model for antiviral testing, and comment on the prospects for its use in future evaluations requiring a poxviral model with a focus on respiratory infection.

Figure 1.

Comparative particle size distributions¹ from aerosol generator used in experimental RPX infection and comparative particle counts of exhaled breath aerosols of a naïve NZW rabbit (inset graph). ¹ Ordinate axis represents the mass of particles between D_p and dlogD_p (D_p = particle diameter). For the particle distribution generated by the nebulizer used in the experimental RPX infection, the transecting line for the distribution represents the mass median aerodynamic diameter (MMAD) and geometric standard deviation (σ_g), respectively. The abscissa axis represents particle size in μm. The particle distributions of the animal’s exhaled breath represent cumulative particle (count) for each discrete size selective bin.

Figure 2.

Two examples of lungs from naïve rabbits exposed to aerosolized RPXV taken at day +6 PI. The lungs are enlarged and heavy with patches of congestion, hemorrhage (arrows) and edema. Discoloration of the lung tissue defines collapsed areas of virally-induced inflammation bordered by light-colored aerated lobules.

Figure 3.

Lung pathology¹ of aerosolized RPX in rabbits. ¹ Lung histologic sections from naïve animals exposed to aerosolized RPXV that died on day +7 PI. (A) alveolar edema and necrosis of adjacent bronchiole (arrow) 50×; (B) diffuse alveolar edema with residual trapped air (200×); (C) severe hemorrhage adjacent to a necrotic airway (50×); (D) severe congestion of capillaries and venules with microhemorrhage (200×); (E) perivascular inflammation (50×); and (F) bronchiolar epithelial necrosis (200×).