%0 Journal Article
%T Targeting the inflammasome and adenosine type-3 receptors improves outcome of antibiotic therapy in murine anthrax
%A Serguei G Popov
%A Taissia G Popova
%A Fatah Kashanchi
%A Charles Bailey
%J World Journal of Biological Chemistry
%D 2011
%I Baishideng Publishing Group Co. Limited
%R 10.4331/wjbc.v2.i5.98
%X AIM: To establish whether activation of adenosine type-3 receptors (A3Rs) and inhibition of interleukin-1¦Â-induced inflammation is beneficial in combination with antibiotic therapy to increase survival of mice challenged with anthrax spores. METHODS: DBA/2 mice were challenged with Bacillus anthracis spores of the toxigenic Sterne strain 43F2. Survival of animals was monitored for 15 d. Ciprofloxacin treatment (50 mg/kg, once daily, intraperitoneally) was initiated at day +1 simultaneously with the administration of inhibitors, and continued for 10 d. Two doses (2.5 mg/kg and 12.5 mg/kg) of acetyl-tyrosyl-valyl-alanyl-aspartyl-chloromethylketone (YVAD) and three doses (0.05, 0.15 and 0.3 mg/kg) of 1-[2-Chloro-6-[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-¦Â-D- ribofuranuronamide (Cl-IB-MECA) were tested. Animals received YVAD on days 1-4, and Cl-IB-MECA on days 1-10 once daily, subcutaneously. Human lung epithelial cells in culture were challenged with spores or edema toxin and the effects of IB-MECA on phosphorylation of AKT and generation of cAMP were tested. RESULTS: We showed that the outcome of antibiotic treatment in a murine anthrax model could be substantially improved by co-administration of the caspase-1/4 inhibitor YVAD and the A3R agonist Cl-IB-MECA. Combination treatment with these substances and ciprofloxacin resulted in up to 90% synergistic protection. All untreated mice died, and antibiotic alone protected only 30% of animals. We conclude that both substances target the aberrant host signaling that underpins anthrax mortality. CONCLUSION: Our findings suggest new possibilities for combination therapy of anthrax with antibiotics, A3R agonists and caspase-1 inhibitors.
%K Anthrax
%K Mice
%K Antibiotics
%K Combination therapy
%K Inflammasome
%K Adenosine 3 receptor agonist
%K Caspase-1 inhibitor
%K AKT
%U http://www.wjgnet.com/1949-8454/full/v2/i5/98.htm