Targeting the inflammasome and adenosine type-3 receptors improves outcome of antibiotic therapy in murine anthrax

作     者：Serguei G Popov Taissia G Popova Fatah Kashanchi Charles Bailey 

作者机构：National Center for Biodefense and Infectious Diseases George Mason UniversityManassasVA 20110Untied States 

出 版 物：《World Journal of Biological Chemistry》 (世界生物化学杂志（英文版）（电子版）)

年 卷 期：2011年第2卷第5期

页      面：98-104页

学科分类：1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100401[医学-流行病与卫生统计学] 10[医学] 

基　　金：Supported by The US Department of Defense grant DAMD17-03-C-0122 

主　　题：Anthrax Mice Antibiotics Combination therapy Inflammasome Adenosine 3 receptor agonist Caspase-1 inhibitor AKT 

摘      要：AIM:To establish whether activation of adenosine type-3 receptors(A3Rs)and inhibition of interleukin- 1β-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 *** treatment(50 mg/kg,once daily,intraperitoneally) was initiated at day+1 simultaneously with the ad- ministration of inhibitors,and continued for 10 *** doses(2.5 mg/kg and 12.5 mg/kg)of acetyl-tyrosylvalyl-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-β-D-ribofuranuronamide(Cl-IB-MECA) were *** 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-MECAon 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 *** treatment with these substances and ciprofloxacin resulted in up to 90%synergistic *** untreated mice died,and antibiotic alone protected only 30% of *** 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.