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

有效铁在慢性弓形虫发展和免疫中的作用

基本信息

批准号：
10371561
负责人：
Jason Gigley
金额：
$ 17.65万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371561
关键词：
Address Affect Antigens Biology Brain CD8-Positive T-Lymphocytes CD8B1 gene Cardiac Myocytes Cell physiology Cells Chronic Cyst Dangerousness Data Development Enterocytes Fibroblasts Foundations Goals Growth Health Heart Human Immune Immune response Immunity Impairment Infection Infection Control Interferon Type II Iron Knowledge Life Location Mediator of activation protein Memory Mission Morbidity - disease rate Mus Muscle Cells Neurons Nutrient Nutritional Immunity Outcome Parasite Control Parasites Parasitic infection Pathway interactions Play Process Public Health Research Role Signal Transduction T cell response T-Cell Activation TFRC gene Testing Toxoplasma gondii Toxoplasmosis United States National Institutes of Health Work adaptive immune response base chronic infection cytokine effector T cell experimental study improved in vivo innovation novel parasitism pathogen response trophoblast uptake

项目摘要

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.

慢性弓形虫（Toxoplasma gondii，T.弓形虫）感染对健康有严重影响，然而，没有有效的从大脑和心脏中消除它们的方法。长期目标是确定机制，慢性T.弓形虫感染的发展和控制，以更好地了解生物学基础T。弓形虫传播、包囊发育、再活化和慢性感染的宿主免疫控制。整体本研究的目的是分析宿主体内有效铁在慢性T细胞白血病发生发展中的作用。弓形虫和免疫反应来控制感染。基本原理是阐明如何主机可用铁工程发展慢性T.弓形虫感染和免疫可为消除弓形虫感染提供强有力的科学依据。寄主有效铁对T.弓形虫感染尚不清楚。初步数据显示，体内可利用的铁导致脑中显著更高的囊肿负荷和有缺陷的CD 8 + T细胞多功能反应。中心假设是宿主可利用铁是调节寄生虫的关键因素传播，慢性囊肿负担和CD 8 + T细胞功能，以控制寄生虫。两个目标将考验假设：1）确定宿主可利用铁如何影响慢性T。弓形虫感染; 2）解剖宿主有效铁影响CD 8 + T细胞对T细胞的免疫力。刚地。目标1将测试减少或增加宿主铁体内影响寄生虫传播、脑和心脏中的囊肿负荷以及小鼠中的慢性感染结果。目的2将检测体内CD 8 + T细胞外源性和内源性铁水平如何影响CD 8 + T细胞的活化、功能分化和慢性T.感染后的弓形虫感染结果。所提出的研究是创新的因为它将定义一个新的过程，即宿主铁如何影响体内寄生虫生物学，新的铁依赖性CD 8 + T细胞内在途径参与对T.弓形虫感染这些高影响实验预计将确定铁如何作用于寄生虫影响慢性T。弓形虫感染以及控制寄生虫传播、包囊负荷和再活化的宿主免疫应答。这些研究解决目前在知识方面存在的重大差距，这些差距是该领域取得进展的主要障碍。