CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection

Abstract

As an obligate intracellular pathogen, the apicomplexan parasiteToxoplasma gondiievades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection withT. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine inT. gondiipathogenesis, we infected wild-type (WT) and CD73−/−mice withT. gondiicysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73−/−mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) protected CD73−/−mice againstT. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73−/−mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limitingT. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A2Awere more susceptible to immunopathology during intraperitoneal infection withT. gondiithan WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.