Caspase-1 controls anthrax lethal toxin-mediated cell lysis and disease progression in rodent models
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Anthrax is a bacterial disease caused by Bacillus anthracis, which has gained notoriety for its potential use as a biological weapon. Anthrax-induced morbidity and mortality in mammalian hosts is associated with the release of Lethal Toxin, LT. In the absence of bacterial infection, LT is able to induce anthrax-like disease in small animal models. We discovered that LT kills select target cells in vitro and in vivo. Dependent on genetic background, LT induced either apoptosis or necrosis in antigen-presenting cells (APCs). We found that LT-mediated apoptosis in macrophages and dendritic cells (DCs) isolated from resistant rodent strains is associated with caspase-3 induction. In contrast, LT triggers rapid necrosis in APCs isolated from susceptible rodent strains such as BALB/c mice and Fisher rats. We further found that LT-mediated necrosis is controlled by the pro-inflammatory protease, caspase-1. Inhibition of caspase-1 by specific inhibitors completely blocked necrosis in LT-treated cells. We were able to block caspase-1 activation and macrophage death by using either caspase-1 specific peptide inhibitors or by using proteasome inhibitors.;Besides processing pro-inflammatory cytokines, we found that caspase-1 is also linked to cytolysis of antigen-presenting cells. Caspase-1 activation in these cells results in necrotic cell death, which is accompanied by a passive efflux of cytosolic proteins. While cells undergoing LT-mediated apoptosis did not show any signs of protein efflux, caspase-1 dependent necrosis resulted in a cytokine burst and a broad release of cytosolic proteins. This is consistent with caspase-1-associated a cytokine release in LT-treated BALB/c mice and F344 rats. We hypothesized that this cytokine burst and release of pro-inflammatory proteins is linked to disease progression and mortality in rats and mice highly susceptible to LT killing.;To determine the role of caspase-1 mediated necrosis and the ensuing cytokine release in LT-induced disease, we treated rats with therapeutic doses of proteasome inhibitors. Strikingly, the proteasome inhibitors salinosporamide A and bortezomib blocked symptoms of vascular collapse associated with LT challenge, including pleural effusion, pulmonary edema, and hemoconcentration. Salinosporamide A also prevented macrophage depletion, interleukin (IL)-18 release and mortality in F344 rats challenged with LT. In contrast, caspase-1-mediated macrophage cytolysis and rapid disease progression did not occur in LT resistant Lewis rats.;Taken together, we propose that caspase-1 activation contributes to LT-mediated vascular collapse and mortality in highly susceptible rats. The finding that proteosome inhibitors block toxin-mediated inflammation and vascular collapse suggests a novel approach for treatment of anthrax, and possibly other inflammatory diseases associated with NLRs.
Source: Dissertation Abstracts International, Volume: 72-06, Section: B, page: 3210.;Advisors: Jurgen Brojatsch.