CD73-generated adenosine limits immunopathology during acute Toxoplasma gondii infection (164.17)

Abstract

Abstract As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii elicits robust innate and adaptive immune responses that must be limited to prevent immunopathology. The breakdown of extracellular ATP to adenosine by the cell-surface enzyme CD73 plays an important role in the resolution of inflammation. The role of extracellular adenosine in the immune response to T. gondii infection has not been previously elucidated. In comparison to wildtype C57BL/6 mice, CD73-knockout mice infected with T. gondii by interperitoneal injection were highly susceptible to immune-mediated pathology, with significantly increased morbidity and mortality associated with marked infiltration of neutrophils and T cells into the peritoneal cavity. Peritoneal exudate cells from infected CD73KO mice generated higher levels of the inflammatory mediators nitric oxide, TNF-alpha, and IL1-beta, without enhanced parasite killing or clearance. The increased morbidity and mortality seen in CD73KO mice could be rescued by treating mice with the broad spectrum adenosine receptor agonist 5'-N-ethylcarboxamido adenosine. In addition, mice deficient in the adenosine receptor A2A were more susceptible to immunopathology during intraperitoneal infection with T. gondii compared to wildtype mice. Thus extracellular adenosine is a key molecule that regulates the immune response to an intracellular pathogen and promotes host survival.