title: Targeting the inflammasome and adenosine type-3 receptors improves outcome of antibiotic therapy in murine anthrax.
abstract: OBJECTIVE
  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 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-β-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.
  
  
  CONCLUSIONS
  Our findings suggest new possibilities for combination therapy of anthrax with antibiotics, A3R agonists and caspase-1 inhibitors.
authors.affiliation: Serguei G Popov, Taissia G Popova, Fatah Kashanchi, Charles Bailey, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, Untied States.
authors.forename: Serguei G
authors.initials: SG
authors.lastname: Popov
authors.forename: Taissia G
authors.initials: TG
authors.lastname: Popova
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey