Role of Available Iron in Development of Chronic Toxoplasma gondii and Immunity

慢性弓形虫(弓形虫)感染对健康有严重影响，但没有有效的 从大脑和心脏中消除它们的方法。长期目标是定义机制，通过这些机制 慢性弓形虫感染发生并得到控制，以更好地了解支撑弓形虫的生物学 慢性感染的传播、包囊发育、再激活和宿主免疫控制。整体而言 这项建议的目的是剖析宿主有效铁在慢性弓形虫和弓形虫发育中的作用。 控制感染的免疫反应。基本原理是阐明宿主可利用铁在发育过程中是如何起作用的 对弓形虫慢性感染和免疫的研究可为消除这种感染提供强有力的科学依据。 宿主有效铁如何影响弓形虫感染尚不清楚。初步数据显示限制主机 体内有效铁导致脑内明显更高的囊性负荷和CD8+T细胞缺陷 多功能反应。中心假设是宿主有效铁是调节寄生虫的关键因素。 传播、慢性包囊负荷和CD8+T细胞功能控制寄生虫。两个目标将考验 假设：1)确定宿主有效铁如何影响慢性弓形虫感染；2)剖析宿主如何 有效铁影响CD8+T细胞对弓形虫的免疫。目标1将测试减少或增加宿主铁 在体内影响寄生虫传播、脑囊和心脏包囊以及小鼠的慢性感染结局。 Aim 2将测试体内CD8+T细胞外源性和内在铁水平如何影响CD8+T细胞的激活、功能 感染后的分化和慢性弓形虫感染结局。本文的研究具有创新性。 因为它将定义一个新的过程，即可利用的宿主铁如何影响体内的寄生虫生物，并确定 新的铁依赖CD8+T细胞内在途径(S)参与弓形虫感染的免疫。这些高 预计冲击实验将定义铁如何作用于影响慢性弓形虫感染的寄生虫，如 以及宿主的免疫反应，以控制寄生虫的传播、包囊负担和复活。这些研究 解决目前知识方面的重大差距，这些差距是该领域取得进展的主要障碍。

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.