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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<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>. 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<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>pathogenesis, we infected wild-type (WT) and CD73<jats:sup>\u2212\/\u2212<\/jats:sup>mice with<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>cysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73<jats:sup>\u2212\/\u2212<\/jats:sup>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\u2032-<jats:italic>N<\/jats:italic>-ethylcarboxamidoadenosine (NECA) protected CD73<jats:sup>\u2212\/\u2212<\/jats:sup>mice against<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73<jats:sup>\u2212\/\u2212<\/jats:sup>mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-\u03b1), and interleukin-1\u03b2 (IL-1\u03b2), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limiting<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>-induced immunopathology. In addition, mice deficient in the adenosine receptor A<jats:sub>2A<\/jats:sub>were more susceptible to immunopathology during intraperitoneal infection with<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>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.<\/jats:p>","DOI":"10.1128\/iai.02536-14","type":"journal-article","created":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T08:05:56Z","timestamp":1417507556000},"page":"721-729","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection"],"prefix":"10.1128","volume":"83","author":[{"given":"Deeqa A.","family":"Mahamed","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon E.","family":"Toussaint","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret S.","family":"Bynoe","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2938"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385526-8.00010-2"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003379"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/260983"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.775"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.226845"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1385\/1-59745-113-4:73"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"4408","DOI":"10.4049\/jimmunol.156.11.4408","article-title":"Adenosine enhances IL-10 secretion by human monocytes","volume":"156","author":"Le Moine O","year":"1996","unstructured":"Le Moine O, Stordeur P, Schandene L, Marchant A, de Groote D, Goldman M, Deviere J. 1996. 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