Therapeutic approaches to bacillus anthracis toxins

Abstract

Bacillus anthracis has three types of infection routes: pulmonary, cutaneous, and gastrointestinal. Naturally occurring infection occurs in all three forms, but there is significant concern with the use of this agent as a biochemical weapon that targets the pulmonary tract. Bacilus anthracis is rapidly fatal and much of the pathology that it induces is exerted through the expression of three toxins: protective antigen (PA), edema factor and lethal factor (LF). PA and LF combine to form lethal toxin (LeTx), which induces lethality. When injected with recombinant LeTx, C57BL/6J mice (age ~3weeks, 14-22 grams) exhibit clinical signs similar to humans infected with anthrax including severe dyspnea, lethargy, impaired gait, seizing, and death. Previous studies of blood chemistry and coagulation panels from animals experiencing advanced clinical signs revealed findings consistent with vessel damage and disseminated intravascular coagulation (DIC). Additionally, immunohistochemical staining for fibrin(ogen), a marker of DIC, was found in multiple organs. Gross and histopathological observations suggested hemorrhage as a common pathological feature. Several interventions targeting vessel leakage, DIC and/or shock were tested in C57BL/6J mice administered recombinant LeTx. Treatments included GM6001 (ilomastat, diNAC) (N,N’-diacetyl-L-cysteine), NAC (N-acetylcysteine, diNAC plus aprotinin, heparin, and heparin plus activated protein C. All of these interventions failed to significantly alter the clinical or gross pathological course of the disease process. It is likely that the pathology induced by LeTx overwhelms interventions aimed at late pathophysiolgical events. Thus, interventions that target earlier steps in the pathophysiology will likely hold more promise in ameliorating disease induced by these toxins.