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COMBINED STIMULATION OF RECEPTORS OF TLR4, TLR9 AND NOD2 SYNERGISTICALLY INCREASES PROTECTION OF LABORATORY MICE IN LETHAL SALMONELLA ENTERICA INFECTION MODEL


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Abstract

Combinations of two or more PRR-agonists can trigger much more intensive immune response than single agonists alone. Synergistic effect of combinations of different PRR-agonists opens new perspectives for immunotherapy of infectious and neoplastic diseases. In this study we investigated the effectiveness of triple combination of TLR4, TLR9 and NOD2 agonists in stimulation of immune responses and protection of BALB/c mice against lethal Salmonella enterica serovar Typhimurium infection. Stimulation of immunity with individual TLR4, TLR9, NOD2 agonists, or their paired TLR9+TLR4, TLR9+NOD2, TLR4+NOD2, or triple TLR9+TLR4+NOD2 combinations was performed before animal challenging with a lethal dose of bacteria. Stimulation of immunity was assessed according to blood immunostimulatory cytokines and chemokines. Combinations of TLR9+TLR4+NOD2, TLR9+TLR4 and TLR4+NOD2 agonists demonstrated maximum protection of animals against a lethal bacterial infection. Injection of TLR9+TLR4+NOD2 agonists provided a survival of 70% (p < 0.01), TLR9+TLR4 ˗ 80% (p < 0.01), and TLR4+NOD2 ≥ 50% (p < 0.05) of animals, while only 10% of animals survived in the challenge control group. No protective activity of single agonists was observed. The anti-infective activity of combinations of ODN2395+LPS and ODN2395+LPS+L18-MDP agonists was accompanied with enhanced production of IL12 in mice and in in vitro culture of mouse macrophages.


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