CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection (56.13)

Abstract

Abstract As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii evades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ecto-enzyme CD73, which generates adenosine in the extracellular matrix, were significantly resistant to acute and chronic toxoplasmosis after oral infection with the T. gondii type II ME49 strain. Resistance in CD73-knockout mice was due to a reduction in immune-mediated pathology in the intestine, and a delay in parasite differentiation in the CNS. To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected wildtype and CD73KO mice with ME49 cysts by the intraperitoneal (IP) route. In contrast to oral infection, IP-infected CD73KO mice were highly susceptible to immune-mediated pathology, with significantly increased 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, TNFα, and IL1β, without enhanced parasite killing or clearance. In addition, mice deficient in the adenosine receptors A1 or 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.