Inhaled anthrax infection is a major bioterrorism threat today. Models that simulate this disease for the study of pathogenesis and treatment are needed. Anthrax infection begins as a local collection of alveolar spores, which then spread as invasive bacteria to the mediastinal structures. From there the infection is disseminated systemically by intravascular spread. Intravascular spread results in a increasing toxin release that contributes directly to death. Anthrax bacilli produce two different virulence factors including a polyglutamate capsule and a 3 components exotoxin. The capsule resists phagocytosis while the toxin is capable of injuring and killing the cells, which it binds to. Macrophage killing by the toxin is important in the spread of the disease. The infection is described as a toxigenic one with most of its pathogenesis relating directly to the toxin or to the toxin?s influence on potentially harmful host mediators. Therefore, animal models based on the toxin alone are capable of simulating many of the key pathogenic events associated with the infection itself. This is important because the toxin can be manipulated far more safely than the bacteria itself. All small animal models to date using toxin challenge, have employed a single rapid bolus. Death in these models is relatively rapid extending from 1 to 3 hs after challenge depending on the dose of toxin. However, such a challenge is not consistent with the natural course of this infection which likely includes a gradual increase in the amount of toxin the host is dealing with. Such increases are reflected in the changes in blood bacteria concentrations that have been observed over time. Thus, an animal model simulating this progressive increase in toxin would better simulate conditions encountered clinically. This in turn would provide a more accurate assessment of evolving pathogenic events associated with toxin and, more importantly, would provide a better model to test the influence of therapies directed at inhibiting the toxin or its effects. The research underway for this project has so far shown that anthrax toxin administered as a 24 h infusion in Sprague-Dawley rats produces a prolonged and significantly different time course in lethality compared to the same weight based bolus dose. A similar pattern of mortality is observed in Fischer animals infused with toxin. Using this model we have shown that in contrast to similarly lethal lipopolysaccharide, anthrax lethal toxin shock is not associated with inflammatory cytokine or nitric oxide release. We have also shown that monocolonal antibody to the protective antigen component of lethal toxin is protective in the model administered up to 12 h after initial exposure to toxin. At present, studies are ongoing determining the nature of the protective effect of PA-Mab. Plans are also underway to compare gene expression patterns with anthrax lethal toxin and LPS, to study the mechanisms underlying the cardiovascular abnormality associated with lethal toxin and to study the effects of conventional hemodynamic support with fluids and vasopressors in the model. It is anticipated that studies will be expanded in a mouse model, where the interactions of the lethal and edema factor components of lethal toxin will be tested.
| Cui, Xizhong; Moayeri, Mahtab; Li, Yan et al. (2004) Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol 286:R699-709 |
