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The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology
The protozoan pathogen Toxoplasma gondii is a highly successful parasite that infects up to a third of the world's population, causing morbidity and mortality in the immunocompromised and when acquired congenitally. As an obligate intracellular pathogen, T. gondii has adapted to acquiring key nutrients from its host. Unlike vertebrate cells which are capable of de novo adenosine synthesis, T. gondii must rely solely on the purine salvage pathway, necessitating the presence of host-generated adenosine. CD73, present on vertebrate host cells but not T. gondii parasites, is a surface-anchored glycoprotein that catalyzes the conversion of AMP to adenosine, which is then sensed by the cell through transmembrane adenosine receptors. The enzyme is highly expressed in various tissues, including the brain, lymphoid organs, and in many immune cell subsets. To determine the role of CD73-generated adenosine in T. gondii infection, I infected wildtype and CD73-knockout mice with the Toxoplasma gondii ME49 strain via the oral route. CD73-/- mice did not succumb to reactivation of infection, and had fewer brain cysts developing in the CD73-/- mice. The reduced cyst burden was due to a defect in T. gondii differentiation to cyst-forming bradyzoites in the brain in the absence of CD73, and was independent of adenosine receptor signaling. In vitro differentiation in primary murine astrocytes and human fibroblasts was also CD73-dependent, and could be rescued by exogenous supplementation with adenosine or blocked with pharmacological inhibition of CD73, while treatment with an adenosine receptor agonist had no effect. Thus CD73- generated adenosine directly promoted T. gondii persistence and differentiation to long-lived tissue cysts. To further investigate the reason for the reduced parasite burden in the CNS, I inoculated WT and CD73-/- mice with T. gondii via peritoneal inoculation. Unexpectedly, CD73-/- mice were markedly susceptible to T. gondii intraperitoneal infection. Susceptibility was associated with elevated IL1[beta], TNF[alpha], IFN[gamma] and nitric oxide production, and increased infiltration of neutrophils and T cells into the peritoneal cavity. CD73 expression on both hematopoietic and nonhematopoietic cells was required to prevent immunopathology, and the absence of CD73 promoted local dissemination of the parasite. Thus, CD73 plays opposite functions in acute and chronic infections with a protozoan pathogen.
Toxoplasma gondii; Extracellular Adenosine; CD73
Bynoe, Margaret S.
August, Avery; Denkers, Eric Young
Ph.D. of Immunology
Doctor of Philosophy
dissertation or thesis