Toxoplasma gondii is an obligate intracellular protozoan pathogen with broad host range and tissue trophism. 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. Limiting access to adenosine may thus affect T. gondii survival or virulence and serve as a potential therapeutic target. CD73, present on vertebrate host cells but not T. gondii parasites, is a surface-anchored glycoprotein that catalyses the conversion of AMP to adenosine, which is then sensed by the cell through transmembrane adenosine receptors. The enzyme is highly expressed on endothelial cells, epithelial cells and lymphocytes. <P>To determine the role of CD73 in T. gondii infection, we infected wild type and CD73- knockout mice with the Toxoplasma gondii ME49 strain via the oral route. We found that while CD73-/- mice were protected from acute T. gondii oral infection, the most significant impact of CD73 was in the CNS, with strikingly attenuated chronic stage infection, (CD73-/- mice did not succumb to reactivation of infection and developed fewer brain cysts). To further investigate the reason for the reduced parasite burden in the CNS, we inoculated WT and CD73-/- mice with T. gondii via peritoneal inoculation. Unexpectedly, CD73-/- mice were markedly susceptible to T. gondii intraperitoneal infection. Our overall hypotheses are that: a) CD73 and CD73-generated adenosine is required for survival or differentiation of T. gondii in the CNS; and b) that CD73 is critical for peritoneal immune regulation in response to local infection. <P>To test these hypotheses, we will study differentiation of T. gondii in CD73-deficient hosts compared to wild type mice (Aim 1). In Aim 2, we will determine the role of CD73 in acute peritoneal infection with T. gondii.
Public Health Relevance: <br/> Toxoplasma gondii is an opportunistic protozoan pathogen that disseminates to the brain following systemic infection. The host immune response is critical for control of infection, but can cause detrimental damage to host tissues if unchecked. In this project, we seek to identify how the host ectoenzyme CD73, and its generation of the immunomodulatory molecule adenosine, impacts Toxoplasma gondii infection during both acute and chronic infections.