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Open Access Highly Accessed Research article

Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment

Yuesheng Li1, Robert A Figler2, Glynis Kolling1, Tara C Bracken1, Jayson Rieger3, Ralph W Stevenson4, Joel Linden5, Richard L Guerrant16 and Cirle Alcantara Warren1*

Author Affiliations

1 Division of Infectious Diseases and International Health, Carter Harrison Bldg, MR6-Rm 2705, 345 Crispell Drive, Charlottesville, VA 22908, USA

2 HemoShear, LLC, Charlottesville, VA, 22908, USA

3 Human Therapeutics Division, Intrexon Corporation, Germantown, MD, 20876, USA

4 Dogwood Pharmaceuticals, Inc., New Haven, CT, 06511, USA

5 Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA

6 University of Virginia, Charlottesville, VA, 22908, USA

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BMC Infectious Diseases 2012, 12:342  doi:10.1186/1471-2334-12-342

Published: 10 December 2012

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.

Conclusion

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.

Keywords:
C. difficile; Colitis; Adenosine A2A receptor; Diarrhea