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Science 320 (5873): 226-230

Copyright © 2008 by the American Association for the Advancement of Science

An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models

Lyudmila G. Burdelya,1* Vadim I. Krivokrysenko,2* Thomas C. Tallant,3 Evguenia Strom,2 Anatoly S. Gleiberman,2 Damodar Gupta,1 Oleg V. Kurnasov,4 Farrel L. Fort,2 Andrei L. Osterman,4 Joseph A. DiDonato,3 Elena Feinstein,2{dagger} Andrei V. Gudkov1,2{dagger}

Abstract: The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor–{kappa}B signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.

1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
2 Cleveland BioLabs, Inc. (CBLI), Buffalo, NY14203, USA.
3 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4 Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: andrei.gudkov{at}; efeinstein{at}

Simvastatin attenuates radiation-induced tissue damage in mice.
X. Zhao, H. Yang, G. Jiang, M. Ni, Y. Deng, J. Cai, Z. Li, F. Shen, and X. Tao (2014)
J Radiat Res 55, 257-264
   Abstract »    Full Text »    PDF »
Gamma-tocopherol-N,N-dimethylglycine ester as a potent post-irradiation mitigator against whole body X-irradiation-induced bone marrow death in mice.
K. Anzai, M. Ueno, K.-i. Matsumoto, N. Ikota, and J. Takata (2014)
J Radiat Res 55, 67-74
   Abstract »    Full Text »    PDF »
Interferon Regulatory Factor-1 in Flagellin-Induced Reprogramming: Potential Protective Role of CXCL10 in Cornea Innate Defense Against Pseudomonas aeruginosa Infection.
G. S. Yoon, C. Dong, N. Gao, A. Kumar, T. J. Standiford, and F.-S. X. Yu (2013)
Invest. Ophthalmol. Vis. Sci. 54, 7510-7521
   Abstract »    Full Text »    PDF »
Combined Stimulation of Toll-Like Receptor 5 and NOD1 Strongly Potentiates Activity of NF-{kappa}B, Resulting in Enhanced Innate Immune Reactions and Resistance to Salmonella enterica Serovar Typhimurium Infection.
A. I. Tukhvatulin, I. I. Gitlin, D. V. Shcheblyakov, N. M. Artemicheva, L. G. Burdelya, M. M. Shmarov, B. S. Naroditsky, A. V. Gudkov, A. L. Gintsburg, and D. Y. Logunov (2013)
Infect. Immun. 81, 3855-3864
   Abstract »    Full Text »    PDF »
Sodium orthovanadate (vanadate), a potent mitigator of radiation-induced damage to the hematopoietic system in mice.
B. Wang, K. Tanaka, A. Morita, Y. Ninomiya, K. Maruyama, K. Fujita, Y. Hosoi, and M. Nenoi (2013)
J Radiat Res 54, 620-629
   Abstract »    Full Text »    PDF »
Flagellin or Lipopolysaccharide Treatment Modified Macrophage Populations after Colorectal Radiation of Rats.
J.-V. Lacave-Lapalun, M. Benderitter, and C. Linard (2013)
J. Pharmacol. Exp. Ther. 346, 75-85
   Abstract »    Full Text »    PDF »
Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist.
L. G. Burdelya, C. M. Brackett, B. Kojouharov, I. I. Gitlin, K. I. Leonova, A. S. Gleiberman, S. Aygun-Sunar, J. Veith, C. Johnson, G. J. Haderski, et al. (2013)
PNAS 110, E1857-E1866
   Abstract »    Full Text »    PDF »
A Multifunctional Chimeric Chaperone Serves as a Novel Immune Modulator Inducing Therapeutic Antitumor Immunity.
X. Yu, C. Guo, H. Yi, J. Qian, P. B. Fisher, J. R. Subjeck, and X.-Y. Wang (2013)
Cancer Res. 73, 2093-2103
   Abstract »    Full Text »    PDF »
Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist.
Z. Hu, Y. Xing, Y. Qian, X. Chen, J. Tu, L. Ren, K. Wang, and Z. Chen (2013)
J Radiat Res 54, 243-250
   Abstract »    Full Text »    PDF »
Chemotherapy-induced mucositis: the role of the gastrointestinal microbiome and toll-like receptors.
D. W. Thorpe, A. M. Stringer, and R. J. Gibson (2013)
Experimental Biology and Medicine 238, 1-6
   Abstract »    Full Text »    PDF »
Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node.
A. Flores-Langarica, J. L. Marshall, J. Hitchcock, C. Cook, J. Jobanputra, S. Bobat, E. A. Ross, R. E. Coughlan, I. R. Henderson, S. Uematsu, et al. (2012)
J. Immunol. 189, 5745-5754
   Abstract »    Full Text »    PDF »
A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease.
X. Ding, G. Bian, N. D. Leigh, J. Qiu, P. L. McCarthy, H. Liu, S. Aygun-Sunar, L. G. Burdelya, A. V. Gudkov, and X. Cao (2012)
J. Immunol. 189, 4719-4727
   Abstract »    Full Text »    PDF »
Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure.
V. I. Krivokrysenko, A. N. Shakhov, V. K. Singh, F. Bone, Y. Kononov, I. Shyshynova, A. Cheney, R. K. Maitra, A. Purmal, M. H. Whitnall, et al. (2012)
J. Pharmacol. Exp. Ther. 343, 497-508
   Abstract »    Full Text »    PDF »
Core circadian protein CLOCK is a positive regulator of NF-{kappa}B-mediated transcription.
M. L. Spengler, K. K. Kuropatwinski, M. Comas, A. V. Gasparian, N. Fedtsova, A. S. Gleiberman, I. I. Gitlin, N. M. Artemicheva, K. A. Deluca, A. V. Gudkov, et al. (2012)
PNAS 109, E2457-E2465
   Abstract »    Full Text »    PDF »
Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner.
M. A. Ciorba, T. E. Riehl, M. S. Rao, C. Moon, X. Ee, G. M. Nava, M. R. Walker, J. M. Marinshaw, T. S. Stappenbeck, and W. F. Stenson (2012)
Gut 61, 829-838
   Abstract »    Full Text »    PDF »
Radiation damage and radioprotectants: new concepts in the era of molecular medicine.
M. I. Koukourakis (2012)
Br. J. Radiol. 85, 313-330
   Abstract »    Full Text »    PDF »
Demand-adapted regulation of early hematopoiesis in infection and inflammation.
H. Takizawa, S. Boettcher, and M. G. Manz (2012)
Blood 119, 2991-3002
   Abstract »    Full Text »    PDF »
Structural Basis of TLR5-Flagellin Recognition and Signaling.
S.-i. Yoon, O. Kurnasov, V. Natarajan, M. Hong, A. V. Gudkov, A. L. Osterman, and I. A. Wilson (2012)
Science 335, 859-864
   Abstract »    Full Text »    PDF »
ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs -- Threshold Doses for Tissue Reactions in a Radiation Protection Context.
F. A. Stewart, A. V. Akleyev, M. Hauer-Jensen, J. H. Hendry, N. J. Kleiman, T. J. MacVittie, B. M. Aleman, A. B. Edgar, K. Mabuchi, C. R. Muirhead, et al. (2012)
Annals of the ICRP 41, 1-322
   Abstract »    PDF »
Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism.
T. E. Riehl, L. Foster, and W. F. Stenson (2012)
Am J Physiol Gastrointest Liver Physiol 302, G309-G316
   Abstract »    Full Text »    PDF »
Bactericidal/Permeability-Increasing Protein (rBPI21) and Fluoroquinolone Mitigate Radiation-Induced Bone Marrow Aplasia and Death.
E. C. Guinan, C. M. Barbon, L. A. Kalish, K. Parmar, J. Kutok, C. J. Mancuso, L. Stoler-Barak, E. E. Suter, J. D. Russell, C. D. Palmer, et al. (2011)
Science Translational Medicine 3, 110ra118
   Abstract »    Full Text »    PDF »
Flagellin, a TLR5 Agonist, Reduces Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation Recipients While Enhancing Antiviral Immunity.
M. S. Hossain, D. L. Jaye, B. P. Pollack, A. B. Farris, M. L. Tselanyane, E. David, J. D. Roback, A. T. Gewirtz, and E. K. Waller (2011)
J. Immunol. 187, 5130-5140
   Abstract »    Full Text »    PDF »
A TLR5 Agonist Inhibits Acute Renal Ischemic Failure.
N. Fukuzawa, M. Petro, W. M. Baldwin III, A. V. Gudkov, and R. L. Fairchild (2011)
J. Immunol. 187, 3831-3839
   Abstract »    Full Text »    PDF »
Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity.
R. M. Jones, V. M. Sloane, H. Wu, L. Luo, A. Kumar, M. V. Kumar, A. T. Gewirtz, and A. S. Neish (2011)
Gut 60, 648-657
   Abstract »    Full Text »    PDF »
Inflammation and p53: A Tale of Two Stresses.
A. V. Gudkov, K. V. Gurova, and E. A. Komarova (2011)
Genes & Cancer 2, 503-516
   Abstract »    Full Text »    PDF »
Toll-Like Receptor 5 Stimulation Protects Mice from Acute Clostridium difficile Colitis.
I. Jarchum, M. Liu, L. Lipuma, and E. G. Pamer (2011)
Infect. Immun. 79, 1498-1503
   Abstract »    Full Text »    PDF »
Sphingosine-1-Phosphate Activates the AKT Pathway to Protect Small Intestines from Radiation-Induced Endothelial Apoptosis.
S. Bonnaud, C. Niaudet, F. Legoux, I. Corre, G. Delpon, X. Saulquin, Z. Fuks, M.-H. Gaugler, R. Kolesnick, and F. Paris (2010)
Cancer Res. 70, 9905-9915
   Abstract »    Full Text »    PDF »
TRIF Mediates Toll-like Receptor 5-induced Signaling in Intestinal Epithelial Cells.
Y. J. Choi, E. Im, H. K. Chung, C. Pothoulakis, and S. H. Rhee (2010)
J. Biol. Chem. 285, 37570-37578
   Abstract »    Full Text »    PDF »
Immediate and Short-, Mid- and Long-term Effects of In Vivo Ionizing Radiation Exposure in BALB/c Mice: I. Activation of Lymphocytes and Subpopulations.
In Vivo 24, 719-726
   Abstract »    Full Text »    PDF »
TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa.
L. Van Maele, C. Carnoy, D. Cayet, P. Songhet, L. Dumoutier, I. Ferrero, L. Janot, F. Erard, J. Bertout, H. Leger, et al. (2010)
J. Immunol. 185, 1177-1185
   Abstract »    Full Text »    PDF »
TRIF Modulates TLR5-dependent Responses by Inducing Proteolytic Degradation of TLR5.
Y. J. Choi, E. Im, C. Pothoulakis, and S. H. Rhee (2010)
J. Biol. Chem. 285, 21382-21390
   Abstract »    Full Text »    PDF »
Reconstitution of a Functional Toll-like Receptor 5 Binding Site in Campylobacter jejuni Flagellin.
M. R. de Zoete, A. M. Keestra, J. A. Wagenaar, and J. P. M. van Putten (2010)
J. Biol. Chem. 285, 12149-12158
   Abstract »    Full Text »    PDF »
Disruption of NF-{kappa}B signalling by ancient microbial molecules: novel therapies of the future?.
F. Yan and D B. Polk (2010)
Gut 59, 421-426
   Full Text »    PDF »
Radioprotectors and Mitigators of Radiation-Induced Normal Tissue Injury.
D. Citrin, A. P. Cotrim, F. Hyodo, B. J. Baum, M. C. Krishna, and J. B. Mitchell (2010)
Oncologist 15, 360-371
   Abstract »    Full Text »    PDF »
Nuclear Factor-{kappa}B (NF-{kappa}B) Is a Novel Positive Transcriptional Regulator of the Oncogenic Wip1 Phosphatase.
J. M. Lowe, H. Cha, Q. Yang, and A. J. Fornace Jr. (2010)
J. Biol. Chem. 285, 5249-5257
   Abstract »    Full Text »    PDF »
Bacterial flagellin stimulates toll-like receptor 5--dependent defense against vancomycin-resistant Enterococcus infection.
M. A. Kinnebrew, C. Ubeda, L. A. Zenewicz, N. Smith, R. A. Flavell, and E. G. Pamer (2010)
The Journal of Infectious Disease 201, 534-543
   Abstract »    Full Text »    PDF »
p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis.
D. G. Kirsch, P. M. Santiago, E. di Tomaso, J. M. Sullivan, W.-S. Hou, T. Dayton, L. B. Jeffords, P. Sodha, K. L. Mercer, R. Cohen, et al. (2010)
Science 327, 593-596
   Abstract »    Full Text »    PDF »
Sodium Orthovanadate Inhibits p53-Mediated Apoptosis.
A. Morita, S. Yamamoto, B. Wang, K. Tanaka, N. Suzuki, S. Aoki, A. Ito, T. Nanao, S. Ohya, M. Yoshino, et al. (2010)
Cancer Res. 70, 257-265
   Abstract »    Full Text »    PDF »
High-Throughput Screening Identifies Two Classes of Antibiotics as Radioprotectors: Tetracyclines and Fluoroquinolones.
K. Kim, J. M. Pollard, A. J. Norris, J. T. McDonald, Y. Sun, E. Micewicz, K. Pettijohn, R. Damoiseaux, K. S. Iwamoto, J. W. Sayre, et al. (2009)
Clin. Cancer Res. 15, 7238-7245
   Abstract »    Full Text »    PDF »
Identification and characterization of oligonucleotides that inhibit Toll-like receptor 2-associated immune responses.
Y.-C. Chang, W.-C. Kao, W.-Y. Wang, W.-Y. Wang, R.-B. Yang, and K. Peck (2009)
FASEB J 23, 3078-3088
   Abstract »    Full Text »    PDF »
Nuclear factor {kappa}B inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos.
B. Daroczi, G. Kari, Q. Ren, A. P. Dicker, and U. Rodeck (2009)
Mol. Cancer Ther. 8, 2625-2634
   Abstract »    Full Text »    PDF »
Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer.
L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle (2009)
Pharmacol. Rev. 61, 177-197
   Abstract »    Full Text »    PDF »
In Vivo 23, 323-336
   Abstract »    Full Text »    PDF »
Signalling loops and linear pathways: NF-{kappa}B activation in response to genotoxic stress.
K. Brzoska and I. Szumiel (2009)
Mutagenesis 24, 1-8
   Abstract »    Full Text »    PDF »
New Molecule Protects Against Radiotoxicity in Rodents and Primates.
Journal Watch (General) 2008, 8
   Full Text »
New Molecule Protects Against Radiotoxicity in Rodents and Primates.
Anthony L. Komaroff, MD and Anthony L. Komaroff, MD (2008)
Journal Watch 2008, JW200804240000008
   Full Text »

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