title: Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment.
abstract: BACKGROUND
  Activation of the A2A adenosine receptor (A2AAR) decreases production of inflammatory cytokines, prevents C. difficile toxin A-induced enteritis and, in combination with antibiotics, increases survival from sepsis in mice. We investigated whether A2AAR activation improves and A2AAR deletion worsens outcomes in a murine model of C. difficile (strain VPI10463) infection (CDI).
  
  
  METHODS
  C57BL/6 mice were pretreated with an antibiotic cocktail prior to infection and then treated with vancomycin with or without an A2AAR agonist. A2AAR-/- and littermate wild-type (WT) mice were similarly infected, and IFNγ and TNFα were measured at peak of and recovery from infection.
  
  
  RESULTS
  Infected, untreated mice rapidly lost weight, developed diarrhea, and had mortality rates of 50-60%. Infected mice treated with vancomycin had less weight loss and diarrhea during antibiotic treatment but mortality increased to near 100% after discontinuation of antibiotics. Infected mice treated with both vancomycin and an A2AAR agonist, either ATL370 or ATL1222, had minimal weight loss and better long-term survival than mice treated with vancomycin alone. A2AAR KO mice were more susceptible than WT mice to death from CDI. Increases in cecal IFNγ and blood TNFα were pronounced in the absence of A2AARs.
  
  
  CONCLUSIONS
  In a murine model of CDI, vancomycin treatment resulted in reduced weight loss and diarrhea during acute infection, but high recurrence and late-onset death, with overall mortality being worse than untreated infected controls. The administration of vancomycin plus an A2AAR agonist reduced inflammation and improved survival rates, suggesting a possible benefit of A2AAR agonists in the management of CDI to prevent recurrent disease.
authors.affiliation: Division of Infectious Diseases and International Health, Carter Harrison Bldg, Charlottesville, VA 22908, USA.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figler
authors.forename: Glynis
authors.initials: G
authors.lastname: Kolling
authors.forename: Tara C
authors.initials: TC
authors.lastname: Bracken
authors.forename: Jayson
authors.initials: J
authors.lastname: Rieger
authors.forename: Ralph W
authors.initials: RW
authors.lastname: Stevenson
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
authors.forename: Cirle Alcantara
authors.initials: CA
authors.lastname: Warren
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001835:Body Weight; D016360:Clostridioides difficile / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control*; D003967:Diarrhea / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D004195:Disease Models, Animal; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055502:Secondary Prevention; D016019:Survival Analysis; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D043705:Receptor, Adenosine A2A; D014640:Vancomycin