Targeted silencing of anthrax toxin receptors protects against anthrax toxins.

Abstract

Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax.

• Authors: Maria T Arévalo, Ashley Navarro, Chenoa D Arico, Junwei Li, Omar Alkhatib, Shan Chen, Diana Diaz-Arévalo, Mingtao Zeng
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 22 Pg. 15730-8 (May 30 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24742682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ANTXR1 protein, human
• ANTXR2 protein, human
• Antigens, Bacterial
• Antxr1 protein, mouse
• Antxr2 protein, mouse
• Bacterial Toxins
• Biomarkers, Tumor
• Microfilament Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Receptors, Cell Surface
• Receptors, Peptide
• anthrax toxin

Topics

• Animals
• Anthrax (genetics, prevention & control)
• Antigens, Bacterial (metabolism, toxicity)
• Bacterial Toxins (metabolism, toxicity)
• Biomarkers, Tumor (genetics, metabolism)
• Bioterrorism
• HEK293 Cells
• Humans
• Macrophages (cytology, physiology)
• Mice
• Microfilament Proteins
• Neoplasm Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptors, Cell Surface (genetics, metabolism)
• Receptors, Peptide (genetics, metabolism)