Research Project
10371561
Chronic Toxoplasma gondii (T. gondii) infections have severe health impacts, however, there are no effective approaches to eliminate them from the brain and heart. The long-term goal is to define mechanisms by which chronic T. gondii infections develop and are controlled to better understand the biology underpinning T. gondii dissemination, cyst development, reactivation, and host immune control of chronic infection. The overall objectives of this proposal are to dissect how host available iron works in development of chronic T. gondii and immune responses to control infection. The rationale is elucidating how host available iron works in development of chronic T. gondii infection and immunity could offer a strong scientific foundation to eliminate this infection. How host available iron affects T. gondii infection is unclear. Preliminary data demonstrates limiting host available iron in vivo results in significantly higher cyst burdens in the brain and defective CD8+ T cell polyfunctional responses. The central hypothesis is that host available iron is a key factor regulating parasite dissemination, chronic cyst burden and CD8+ T cell function to control the parasite. Two aims will test the hypothesis: 1) Identify how host available iron affects chronic T. gondii infection; and 2) Dissect how host available iron affects CD8+ T cell immunity to T. gondii. Aim 1 will test how decreasing or increasing host iron in vivo affects parasite dissemination, cyst burdens in brain and heart and chronic infection outcomes in mice. Aim 2 will test how CD8+ T cell extrinsic and intrinsic iron levels in vivo affects CD8+ T cell activation, function and differentiation and chronic T. gondii infection outcomes after infection. The research proposed is innovative because it will define a novel process of how available host iron impacts parasite biology in vivo and identify novel iron dependent CD8+ T cell intrinsic pathway(s) involved in immunity to T. gondii infection. These high impact experiments are expected to define how iron acts on the parasite impacting chronic T. gondii infection as well as the host immune response to control parasite dissemination, cyst burden and reactivation. These studies address significant current gaps in knowledge that are major barriers to progress in the field.
