Driver of anthrax toxicity could lead to late-stage therapy

A study in the March 24 Cell reports the discovery of a gene that drives anthrax bacteria's toxic effects. The gene could offer a potential new target for countermeasures against the lethal toxin, according to the researchers.

Such therapies might have the potential to protect against anthrax during the late stages of the disease, after antibiotics have lost their therapeutic value, they added.

The team found that human cells deficient in the so-called LDL receptor-related protein (LRP6) become resistant to anthrax toxin. Furthermore, antibodies against LRP6 protected cells from anthrax toxicity, reported study authors Wensheng Wei and Stanley Cohen of the Stanford University School of Medicine in collaboration with others at Stanford and the National Institutes of Health. The level of anthrax protection afforded by the antibodies rose with increasing dose.

Anthrax is a lethal disease of humans and other animals caused by the spore-forming bacteria Bacillus anthracis, which has been the focus of biological interest and bioterrorism concern. The virulence of the bacteria depends on separate complexes formed by interaction of a carrier protein, protective antigen, with lethal and edema factors responsible for the toxic effects and swelling that impairs the host's immune response.

In the current study, the researchers inactivated genes randomly in human cells. They then examined the mutated cells for resistance to anthrax toxin in an effort to identify host genes that have important roles in infection, with the hope of finding possible new targets for therapies aimed at the host instead of the bacteria. The method allows for the identification of required host cell genes without pre-conceptions about their potential to play a role, the study authors said.

The study revealed that LRP6 acts as a co-receptor, enabling cells to take up anthrax toxin through its interactions with two distinct cell- surface proteins earlier shown to bind the "protective antigen carrier" of anthrax toxin, allowing its delivery into cells.

The new findings "reveal a previously unsuspected biological role" for LRP6, a gene earlier found to play important roles in pathways underlying early development and cell proliferation, the researchers said. The discovery also suggests potential new avenues for treating late-stage anthrax disease, they added.

While antibiotics, such as Cipro, can fight the anthrax bacteria when the disease is caught early, such drugs do nothing to dispel the accumulated toxin, the researchers explained. In contrast, drugs that target the host protein LRP6, or other components of the host machinery integral to the toxin's internalization, might offer a novel method to prevent the toxin from infiltrating and killing cells.

"Our discovery of the role of LRP6 in anthrax toxicity and the demonstration that antibodies directed against the extracellular domain of LRP6 can protect cells grown in culture against killing by anthrax toxin suggest that the immunological targeting of LRP6 may prove useful in protecting against the effects of accumulated toxin during the late stages of anthrax disease when antibacterial methods normally are no longer of therapeutic value," the researchers wrote.

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Wensheng Wei, Quan Lu, and Stanley N. Cohen of Stanford University School of Medicine in Stanford, CA; G. Jilani Chaudry of the National Institute of Allergy and Infectious Diseases, National Institutes of Health in Bethesda, MD and the University of Texas at San Antonio in San Antonio, TX; Stephen H. Leppla of the National Institute of Allergy and Infectious Diseases, National Institutes of Health in Bethesda, MD. These investigations were supported by California Breast Cancer Research Program grants to W.W. and Q.L. and by a grant from the Defense Advanced Research Projects Agency (DARPA) to S.N.C.

Wei et al.: "The LDL Receptor-Related Protein LRP6 Mediates Internalization and Lethality of Anthrax Toxin." Publishing in Cell 124, 11411154, March 24, 2006. DOI 10.1016/j.cell.2005.12.045 www.cell.com


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