Abstract
After tissue injury or infection, high levels of ATP inside cells is liberated and can serve as a danger signal that activates immune cells and promotes inflammation. The subsequent breakdown of extracellular ATP to adenosine by the cell-surface enzyme CD73 plays an important role in the resolution of the inflammatory response. Interestingly, the protozoan pathogen Toxoplasma gondii requires host adenosine for its purine needs as it cannot synthesize purines de novo. The role of extracellular adenosine in the immune response to T. gondii infection has not been previously elucidated. To investigate the role of CD73-generated adenosine in the immune response to infection with Toxoplasma gondii, wild-type C57BL/6 and CD73-/- mice were inoculated with T. gondii cysts by intragastric gavage. CD73-/- mice were less susceptible to T. gondii infection, with reduced intestinal inflammation and tissue damage during the acute stages of infection, and reduced parasite burden in the brain during chronic infection. In addition, cysts isolated from infected CD73-knockout mice were attenuated in their ability to cause pathology and mortality when inoculated into naïve wildtype or CD73-/- mice. In vitro, peritoneal macrophages and bone-marrow derived dendritic cells lacking CD73 were less permissive to the intracellular replication of T. gondii tachyzoites. These findings are the first to demonstrate that lack of CD73-generated adenosine impairs T. gondii pathogenesis.
