title: Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2).
abstract: Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios.
authors.affiliation: Cleveland BioLabs, Inc., Buffalo, New York, United States of America. ashakhov@cbiolabs.com
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Shakhov
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Singh
authors.forename: Frederick
authors.initials: F
authors.lastname: Bone
authors.forename: Alec
authors.initials: A
authors.lastname: Cheney
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Kononov
authors.forename: Peter
authors.initials: P
authors.lastname: Krasnov
authors.forename: Troitza K
authors.initials: TK
authors.lastname: Bratanova-Toshkova
authors.forename: Vera V
authors.initials: VV
authors.lastname: Shakhova
authors.forename: Jason
authors.initials: J
authors.lastname: Young
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weil
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Baker
authors.forename: Andrei
authors.initials: A
authors.lastname: Gudkov
authors.forename: Elena
authors.initials: E
authors.lastname: Feinstein
mesh_terms: D054508:Acute Radiation Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016207:Cytokines / Q000097:blood; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D057809:HEK293 Cells; D006413:Hematopoietic System / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D055666:Lipopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009174:Mycoplasma / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D055666:Lipopeptides; D051195:Toll-Like Receptor 2; D016179:Granulocyte Colony-Stimulating Factor