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CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection. | LitMetric

CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection.

Infect Immun

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA

Published: February 2015

AI Article Synopsis

  • * Mice lacking CD73 (CD73(-/-)) were resistant to chronic toxoplasmosis when infected orally, but showed increased susceptibility to immune responses during systemic infections, leading to higher inflammation and tissue damage.
  • * The study shows that extracellular adenosine plays a critical role in regulating immune responses, as its absence in CD73(-/-) mice resulted in higher inflammatory markers without improving parasite clearance, emphasizing the need for balanced immune regulation to prevent tissue damage.

Article 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 ectoenzyme 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 central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected wild-type (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 5'-N-ethylcarboxamidoadenosine (NECA) protected CD73(-/-) mice against T. 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 limiting T. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A(2A) were more susceptible to immunopathology during intraperitoneal infection with T. gondii than WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294259PMC
http://dx.doi.org/10.1128/IAI.02536-14DOI Listing

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