Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

Abstract

Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. 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. No changes in TNF-α occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. 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

Contribution of toxins to the pathogenesis of inhalational anthrax

“…One major feature observed on autopsy is extensive haemorrhaging of the lymphoid organs (such as the lymph nodes and spleen) (Guarner et al, 2003). Studies in a mouse model have shown that LT injection induces thrombopenia (Moayeri et al, 2003), associated with a slower clotting time, a decrease in fibrinogenaemia and the accumulation of fibrin deposits in tissue sections (Culley et al, 2005). These autopsy findings are consistent with recent reports showing that LT and ET extensively disrupt platelet function and aggregation (Kau et al, 2005;Alam et al, 2006).…”

Differentiation of human monocytic cell lines confers susceptibility to Bacillus anthracis lethal toxin

“…Circulating monocyte levels were also unaffected in LT-treated rats, although measurements were taken only 3 h and 9 h after administration (Cui et al, 2004). In LT-treated mice, however, a rapid depletion of monocytes was observed, but the cause of this depletion was not investigated (Moayeri et al, 2003).…”

“…Evasion of the host innate immune response by triggering macrophage cell death is a common strategy used by a number of bacterial pathogens including Shigella, Salmonella and Yersinia (Navarre and Zychlinsky, 2000). Although LT-induced death of macrophages does not appear to play a role in how animals die of anthrax (Moayeri et al, 2003;Cui et al, 2004), it may be a strategy used by B. anthracis to establish an infection. Our results indicate that LT-induced death of a human monocytic cell line depends on its differentiation state and occurs through a mechanism that is distinct from those that occur in mouse macrophages.…”

The host response to anthrax lethal toxin: unexpected observations

“…The β test described here by Amberg et al (7) further highlights the unique, localized Ca 2+ signaling mechanism in vascular myocytes and the role of the β subunit in tuning the Ca 2+ sensitivity of the BK channel complex. Functional changes in coupling between the SR and the sarcolemma, resulting from the altered expression of BK β subunits, may be a key mechanism underlying variations in vascular tone in vivo.…”