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Infection and Immunity, January 2009, p. 348-359, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01005-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inactivation of Rho GTPases by Statins Attenuates Anthrax Lethal Toxin Activity {triangledown}

Aimee M. deCathelineau{dagger} and Gary M. Bokoch*

Department of Immunology and Microbial Science and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Received 11 August 2008/ Returned for modification 18 September 2008/ Accepted 10 October 2008

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.

* Corresponding author. Mailing address: The Scripps Research Institute, 10550 N. Torrey Pines Road, IMM14/R211, La Jolla, CA 92037. Phone: (858) 784-8217. Fax: (858) 784-8218. E-mail: bokoch{at}scripps.edu

{triangledown} Published ahead of print on 20 October 2008.

Editor: B. A. McCormick

{dagger} Present address: Rockefeller University Press, 1114 First Ave., 3rd Fl., New York, NY 10065.

Infection and Immunity, January 2009, p. 348-359, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01005-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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