Anthrax lethal toxin co-complexes are stabilized by contacts between adjacent lethal factors

ABSTRACT Anthrax lethal factor (LF), secreted by Bacillus anthracis, interacts with protective antigen to form a bipartite toxin (lethal toxin [LT]) that exerts pleiotropic biological effects resulting in subversion of the innate immune response. Although the mitogen-activated protein kinase kinases (MKKs) are the major intracellular protein targets of LF, the pathology induced by LT is not well understood. The statin family of HMG-coenzyme A reductase inhibitors have potent anti-inflammatory effects independent of their cholesterol-lowering properties, which have been attributed to modulation of Rho family GTPase activity. The Rho GTPases regulate vesicular trafficking, cytoskeletal dynamics, and cell survival and proliferation. We hypothesized that disruption of Rho GTPase function by statins might alter LT action. We show here that statins delay LT-induced death and MKK cleavage in RAW macrophages and that statin-mediated effects on LT action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, did not significantly affect LT binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of LT once internalized. The use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during B. anthracis infection.

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Faculty Opinions recommendation of Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028790.342344 ◽

2005 ◽

Author(s):

Drusilla L Burns

Keyword(s):

Drug Design ◽

Protective Antigen ◽

Lethal Toxin ◽

Anthrax Lethal Toxin

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Calcium is required for the expression of anthrax lethal toxin activity in the macrophagelike cell line J774A.1.

Infection and Immunity ◽

10.1128/iai.57.7.2107-2114.1989 ◽

1989 ◽

Vol 57 (7) ◽

pp. 2107-2114 ◽

Cited By ~ 44

Author(s):

R Bhatnagar ◽

Y Singh ◽

S H Leppla ◽

A M Friedlander

Keyword(s):

Cell Line ◽

Lethal Toxin ◽

Anthrax Lethal Toxin ◽

Macrophagelike Cell

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Mouse Susceptibility to Anthrax Lethal Toxin Is Influenced by Genetic Factors in Addition to Those Controlling Macrophage Sensitivity

Infection and Immunity ◽

10.1128/iai.72.8.4439-4447.2004 ◽

2004 ◽

Vol 72 (8) ◽

pp. 4439-4447 ◽

Cited By ~ 75

Author(s):

Mahtab Moayeri ◽

Nathaniel W. Martinez ◽

Jason Wiggins ◽

Howard A. Young ◽

Stephen H. Leppla

Keyword(s):

Genetic Factors ◽

Inbred Mouse ◽

Inbred Strains ◽

Lethal Toxin ◽

Cytokine Response ◽

Mouse Strains ◽

Anthrax Lethal Toxin ◽

Toll Like Receptor 4 ◽

Oxide Synthase

ABSTRACT Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (Mφ) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT Mφ sensitivity Kif1C locus to analyze the role of Mφ sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1β occurred only in mice having LT-sensitive Mφ. However, while iNOS knockout C57BL/6J mice having LT-sensitive Mφ were much more susceptible to LT than the knockout mice with LT-resistant Mφ, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between Mφ sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive Mφ and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant Mφ and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires Mφ lysis and while Mφ sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of Mφ sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling Mφ lysis and cytokine response and is independent of Tlr4 function.

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