Wednesday, December 03, 2014

CD73-Generated Adenosine is Critical for Immune Regulation During Toxoplasma gondii Infection

2014 Dec 1. pii: IAI.02536-14. [Epub ahead of print]
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 resistant to chronic toxoplasmosis after oral infection with T. gondii. Resistance in CD73-knockout mice was due to a delay in parasite differentiation in the CNS. To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected WT and CD73-/- mice with T. gondii cysts 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 NECA protected CD73-/- mice against T. gondii induced immunopathology, suggesting 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, TNFα, and IL1β, without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression on both hematopoietic and nonhematopoietic compartments contributes to limiting T. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A2A were more susceptible to immunopathology during intraperitoneal infection with T. gondii, compared to WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage to an intracellular pathogen and promotes host survival.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
[PubMed - as supplied by publisher]

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