In vivo efficacy of a phosphodiester TLR-9 aptamer and its beneficial effect in a pulmonary anthrax infection model.
Immunostimulatory oligonucleotide (ISS-ODN) used as adjuvants are commonly modified with phosphorothioate (PS). The PS backbone prevents nuclease degradation, but confers undesired side effects, including systemic cytokine release. Previously, R10-60, a phosphodiester (PO) ISS-ODN, was structurally optimized as an intracellular Toll-like receptor-9 agonist. Here intravenous, intradermal and intranasal administration of PO R10-60 elicit local or adaptive immune responses with minimal systemic effects compared to a prototypic PS ISS-ODN in mice. Furthermore, prophylactic intranasal administration of PO R10-60 significantly delayed death in mice exposed to respiratory anthrax comparable to the PS ISS-ODN. The pattern of cytokine release suggested that early IL-1beta production might contribute to this protective effect, which was replicated with recombinant IL-1beta injections during infection. Hence, the transient effects from a PO TLR-9 agonist may be beneficial for protection in a bacterial bioterrorism attack, by delaying the onset of systemic infection without the induction of a cytokine syndrome.
Wu
Christina C N
CC
Department of Medicine, Rebecca and John Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093-0820, USA. c5wu@ucsd.edu
Sabet
Mojgan
M
Hayashi
Tomoko
T
Tawatao
Rommel
R
Fierer
Joshua
J
Carson
Dennis A
DA
Guiney
Donald G
DG
Corr
Maripat
M
D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D052157:Aptamers, Nucleotide / Q000235:genetics / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D007700:Kinetics; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013171:Spores, Bacterial / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000276:immunology
D052157:Aptamers, Nucleotide; D016207:Cytokines; D007074:Immunoglobulin G; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9