CD73-generated extracellular adenosine regulates Toxoplasma gondii infection via NKT cell cytokine production. (P3057)

Abstract

Abstract Toxoplasma gondii is an apicomplexa, obligate intracellular pathogen that evades the host immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. We have previously shown that mice deficient in the ecto-enzyme CD73, which generates extracellular adenosine, were significantly resistant to acute and chronic toxoplasmosis after oral infection with the T. gondii type II ME49 strain. Resistance in CD73KO mice was due to a defect in parasite differentiation in the central nervous system (CNS). In contrast to oral infection, intraperitoneal infected CD73KO mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. The adenosine receptor agonist NECA offered protection against immunopathology in infected CD73-/- mice, suggesting the absence of CD73-generated adenosine led to increased susceptibility in these mice. Peritoneal exudate cells from infected CD73KO mice generated higher levels of the inflammatory mediators nitric oxide, TNFα, IL1β and IFNγ. Interestingly, despite the high IFNγ in CD73-/- mice, they produced little to no IL-12. We propose that the IFNγ production independent of IL-12 in these mice during T. gondii infection may be produced by NKT cells (proficient producers of IFNγ). Thus extracellular adenosine is a key molecule that regulates the immune response to an intracellular pathogen and promotes host survival.