Murine Aerosol Challenge Model of Anthrax

Abstract

The availability of relevant and useful animal models is critical for progress in the development of effective vaccines and therapeutics. The infection of rabbits and non-human primates with fully virulent Bacillus anthracis spores provides two excellent models of anthrax disease. However, the high cost of procuring and housing these animals and the specialized facilities required to deliver fully virulent spores limit their practical use in early stages of product development. Conversely, the small size and low cost associated with using mice makes this animal model more practical for conducting experiments in which large numbers of animals are required. In addition, the availability of knockout strains and well-characterized immunological reagents makes it possible to perform studies in mice that cannot be performed easily in other species. Although we, along with others, have used the mouse aerosol challenge model to examine the outcome of B. anthracis infection, a detailed characterization of the disease is lacking. The current study utilizes a murine aerosol challenge model to investigate disease progression, innate cytokine responses, and histological changes during the course of anthrax after challenge with aerosolized spores. Our results show that anthrax disease progression in a complement-deficient mouse after challenge with aerosolized Sterne spores is similar to that described for other species, including rabbits and non-human primates, challenged with fully virulent B. anthracis. Thus, the murine aerosol challenge model is both useful and relevant and provides a means to further investigate the host response and mechanisms of B. anthracis pathogenesis.

Pathology of Inhalational Anthrax Animal Models

“…Only recently have true murine inhalational models been described in the literature. 16,38,40,46 Even fewer reports have described mice aerosolized with fully virulent B anthracis. 16,38 Currently, there are two mouse models used to understand a number of aspects of the pathogenesis of aerosolized anthrax.…”

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

“…However, when the clonal proportions were analyzed both within the focal region and in the non-luminescent regions, all clonal populations were present and when averaged were not significantly different from the inoculum. This suggests that while our mice had fewer spores reach the lungs compared to previously published amounts in aerosol models, all clonal identities were capable of reaching the focal regions [295]. As such, the bottlenecks detected in the focal region are unlikely to occur due to uneven delivery of the spores to the lungs.…”

“…Since the Sterne strain lacks the pX02 plasmid encoding the anti-phagocytic capsule, the experiments can be performed without the difficulties of BSL-3 facilities, providing a more economical model of study. Additionally, several studies have noted key similarities between the A/J mouse model of anthrax with larger animal models [103,104,270,275,295]. These include a similar dissemination pattern and a high level of bacteremia within the host [270,275,295].…”

“…mice are useful models to analyze colonization and early steps in pathogenesis [96,295]. A disadvantage, however, is the lack of capsule, which is thought to account for pathological differences found during the bacteremic stages of infection.…”

“…Therefore, previous damage to the lungs may skew infections to germinate and disseminate from the lungs, rather than disseminate from the NALT or lymphatics. Conversely, there is support for lymphatic dissemination from the lungs since large scale germination does not occur in the lungs and there is no sign of bronchiopneumonia [74,274,[283][284][285]295]. A central caveat to previous pathological analyses and determination of bacterial burden is that the infection was analyzed either at defined time points or after death and in particular organs.…”