In fact, the ability of macrophages to produce these factors in response to classic stimuli, such as LPS, is actually inhibited by LT treatment ( 20). However, in recent years various laboratories have been unable to induce production of inflammatory cytokines by LT-treated toxin-sensitive macrophages in vitro at the RNA or protein level ( 19). Thus, many investigators are focusing on anticytokine therapies similar to those used for sepsis. This view of macrophage-dependent pathogenesis has been widely cited and has influenced many studies being initiated to identify therapies for treatment of anthrax infections. Reports that very low doses of LT induce sensitive macrophages to produce TNF-α and IL-1β in vitro, along with the ability of an IL-1 antagonist or a mixture of antisera to TNF-α and IL-1β to protect mice from LT challenge, led to the suggestion of a macrophage-dependent endotoxic shock–like death in anthrax ( 18). to conclude that macrophage sensitivity was a requirement for LT-mediated toxicity in mice ( 18). Later, macrophage depletion experiments in BALB/c mice led Hanna et al. The discovery that inbred mouse strains differed in their relative susceptibility to LT, and that this correlated with the LT sensitivity of their macrophages, implicated this cell in the pathogenesis of LT ( 17). anthracis strains lacking individual toxin components proved that LT is the major virulence factor in mice ( 15, 16). Humans and primates infected by aerosol exposure to spores present pleural effusions as the most common symptom of disease ( 9– 14).Ĭomparison of mutated B. Pulmonary edema has also been associated with many models of LT-mediated lethality, including the uniquely rapid death of Fischer 344 rats ( 8). Lethal toxin (LT), the combination of LF and PA, is sufficient to induce many of the laboratory manifestations of anthrax disease in animal models ( 2– 6).Įarly studies suggested that LT killed animals by inducing nonspecific shocklike manifestations and vascular leakage ( 2, 7). PA is required for binding and translocation of these enzymatic moieties into target cells (for review, see ref. EF (an adenyl cyclase) and LF (a protease) are toxic only when combined with PA. Anthrax toxin, the major virulence factor of this organism, consists of three polypeptides: edema factor (EF), lethal factor (LF), and protective antigen (PA). IntroductionĪnthrax, the disease caused by Bacillus anthracis, is a worldwide bioterrorism concern. The evidence presented shows that LT kills mice through a TNF-α–independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The C57BL/6J mice did not mount a similar cytokine response. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1β. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. There was no evidence of disseminated intravascular coagulation or renal dysfunction.
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Crisis was due to extensive liver necrosis accompanied by pleural edema. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. We studied LT toxicity in BALB/cJ and C57BL/6J mice. Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals.