Flagellin treatment protects against chemicals, bacteria, viruses, and radiation.
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-alpha. 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.
Department of Pathology, Emory University, Atlanta, GA 30322, USA.
Matam
M
Vijay-Kumar
Jesse D
JD
Aitken
Catherine J
CJ
Sanders
Amena
A
Frias
Valerie M
VM
Sloane
Jianguo
J
Xu
Andrew S
AS
Neish
Mauricio
M
Rojas
Andrew T
AT
Gewirtz
D000284:Administration, Oral; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000008:administration & dosage* / Q000009:adverse effects; D005408:Flagellin / Q000008:administration & dosage* / Q000627:therapeutic use; D005720:Gamma Rays / Q000009:adverse effects; D007113:Immunity, Innate / Q000187:drug effects / Q000528:radiation effects; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D012400:Rotavirus Infections / Q000276:immunology / Q000517:prevention & control*; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000517:prevention & control*; D051198:Toll-Like Receptor 5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011837:Radiation-Protective Agents; D051198:Toll-Like Receptor 5; D005408:Flagellin; D016264:Dextran Sulfate