title: 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.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Arévalo
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Ashley
authors.initials: A
authors.lastname: Navarro
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Chenoa D
authors.initials: CD
authors.lastname: Arico
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Junwei
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Omar
authors.initials: O
authors.lastname: Alkhatib
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Diana
authors.initials: D
authors.lastname: Diaz-Arévalo
authors.affiliation: From the Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905 mt.zeng@ttuhsc.edu.
authors.forename: Mingtao
authors.initials: M
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000881:Anthrax / Q000235:genetics / Q000517:prevention & control; D000942:Antigens, Bacterial / Q000378:metabolism / Q000633:toxicity*; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D023482:Bioterrorism; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism
chemical_list: C473287:ANTXR1 protein, human; C447150:ANTXR2 protein, human; D000942:Antigens, Bacterial; C523012:Antxr1 protein, mouse; C523013:Antxr2 protein, mouse; D001427:Bacterial Toxins; D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C030325:anthrax toxin
keywords: Anthrax Toxin; Bacterial Toxin; Macrophage; RNA Interference (RNAi); RNA Silencing; Receptor
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