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Flagellin Treatment Protects against Chemicals, Bacteria, Viruses, and Radiation¹

Matam Vijay-Kumar^*, Jesse D. Aitken^*, Catherine J. Sanders^*, Amena Frias^*, Valerie M. Sloane^*, Jianguo Xu, Andrew S. Neish^*, Mauricio Rojas and Andrew T. Gewirtz^2,*

^* Department of Pathology and Department of Medicine, Emory University, Atlanta, GA 30322

Sudden exposure of human populations to chemicals, pathogens, or radiation has the potential to result in substantial morbidity. A potential means of rapidly protecting such populations might be to activate innate host defense pathways, which can provide broad protection against a variety of insults. However, innate immune activators can, by themselves, result in severe inflammatory pathology, which in large part is driven by hemopoietic-derived cytokines such as TNF-. We reasoned that, because it preferentially activates epithelial cells, the TLR5 agonist flagellin might not induce severe inflammatory pathology and yet be an ideal agent to provide such non-specific protection, particularly at the mucosal surfaces that serve as a front line of host defense. In accordance, we observed that systemic treatment of mice with purified flagellin did not induce the serologic, histopathologic, and clinical hallmarks of inflammation that are induced by LPS but yet protected mice against chemicals, pathogens, and ionizing radiation. Flagellin-elicited radioprotection required TLR5, the TLR signaling adaptor MyD88, and was effective if given between 2 h before to 4 h after exposure to irradiation. Flagellin-elicited radioprotection was, in part, mediated via effects on cells in bone marrow but yet rescued mortality without a pronounced rescue of radiation-induced anemia or leukopenia. Thus, systemic administration of flagellin may be a relatively safe means of providing temporary non-specific protection against a variety of challenges.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a National Institutes of Health Grant (DK061417 to A.T.G.). M.V.-K. is a recipient of Research Fellowship from Crohn’s and Colitis Foundation of America. This research used National Institutes of Health Digestive Disease Research and Development Center that is supported by National Institutes of Health Grant DK064399.

² Address correspondence and reprint requests to Dr. Andrew T. Gewirtz, Department of Pathology, Emory University School of Medicine, Whitehead Biomedical Research Building, Suite 105H, 615 Michael Street, Atlanta, GA 30322. E-mail address: agewirt{at}emory.edu

³ Abbreviations used in this paper: DC, Dendritic cell; FER, flagellin-elicited radioprotection; DSS, dextran sodium sulfate; CBC, complete blood-cell count; BMC, bone marrow cells.