Abstract
BACKGROUND: Anthrax, caused by Bacillus anthracis, leads to severe sepsis due to multiple virulence factors, including toxins and bacterial cell wall components, which disrupt immune responses and induce cytotoxic effects. However, the relative contributions of toxins vs bacterial overload during systemic disease remain unclear. OBJECTIVES: We aimed to investigate the differential effects of toxigenic B anthracis Sterne strains and nontoxigenic ΔSterne strains on coagulation, complement activation, immune response, endothelial function, and organ damage in a baboon model of anthrax. METHODS: Healthy baboons were intravenously infused with a sublethal dose (1 × 10(8) colony-forming units/kg) of either B anthracis Sterne or ΔSterne strains. Animals were monitored for 7 days and assessed for vital signs, hematologic parameters, coagulation markers, endothelial dysfunction, complement activation, and proteomic profiles. RESULTS: The toxigenic Sterne strain induced more severe systemic effects than the ΔSterne strain, including prolonged bacterial persistence, enhanced coagulopathy, increased complement activation, endothelial dysfunction, neutrophil activation, and neutrophil extracellular trap formation. Coagulopathy was evidenced by elevated protease-antithrombin complexes, prolonged clotting times, fibrinogen consumption, and thrombocytopenia. Proteomic analysis of plasma revealed stronger upregulation of proteins involved in innate immunity, metabolism, coagulation, and cell death pathways in Sterne animals compared with ΔSterne-challenged animals. CONCLUSION: Our findings suggest that anthrax toxins contribute to the exacerbation of pathological host responses during anthrax sepsis, including coagulopathy, complement activation, endothelial dysfunction, and organ injury. These observations provide insight into the role of toxins in intensifying disease severity beyond bacterial burden alone. Therapeutic strategies targeting coagulation and complement pathways, while preserving endothelial function, may help mitigate anthrax-induced sepsis.