Iron regulation of chronic Toxoplasma gondii infection and immunity

铁对慢性弓形虫感染和免疫的调节

基本信息

批准号：
10362711
负责人：
DAVID J BZIK
金额：
$ 21.91万
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：
2021-03-02 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362711
关键词：
3&apos Untranslated Regions Aconitate Hydratase Acquired Immunodeficiency Syndrome Acute Address Affect Binding Biology Brain CD8-Positive T-Lymphocytes Cell physiology Cells Cellular Immunity Cessation of life Chronic Cyst Data Development Effectiveness Enterocytes Exhibits Frequencies Gene Expression Gene Proteins Genes Genetic Transcription Granzyme Hospitalization Immune Immune response Immunity In Vitro Inbred BALB C Mice Individual Infection Infection Control Interferon Type II Iron Iron-Regulatory Proteins Knowledge Messenger RNA Mission Mitochondria Molecular Morbidity - disease rate Mus Neuraxis Neurons Nutrient Oocysts Oral Ingestion Parasites Pharmaceutical Preparations Population Proteins Public Health Regulation Response Elements Role Signal Transduction Stress T cell response T-Lymphocyte TFRC gene Testing Toxoplasma Toxoplasma gondii Toxoplasmosis United States United States National Institutes of Health acute infection cell mediated immune response cell type chronic infection experimental study foodborne pathogen improved in vivo iron deficiency novel prevent toxoplasmic encephalitis

项目摘要

Toxoplasma gondii (Toxoplasma) causes an acute infection characterized by replicating tachyzoites that eventually develops into a chronic infection characterized by persisting bradyzoite stage Toxoplasma cysts in the brain and central nervous system. Chronic Toxoplasma infection affects ~30% of the United States population and during immune deficiency cysts reactivate and cause a severe Toxoplasmic encephalitis. There are currently no drugs or therapies that are effective at preventing cyst development or eliminating cysts in chronically infected individuals. The biology underpinning Toxoplasma cyst development, reactivation, and host immune control of acute and chronic infection is still poorly understood. From current evidence and preliminary data, we hypothesize that iron availability regulates parasite differentiation, cyst reactivation, and the effectiveness of the CD8+ T cell immune response in controlling acute infection and in preventing cyst reactivation. In Aim 1 we will investigate the role of iron sensing by the Toxoplasma Iron Regulatory Protein in differentiation and cyst reactivation. In Aim 2 we will investigate the role of iron availability in the development of CD8+ T cell mediated immunity and in the control of chronic cysts by CD8+ T cells. These two specific aims will test our novel hypothesis that iron regulates parasite stage differentiation and host immunity to acute and chronic infection. These high impact experiments are expected to define key iron regulated mechanisms that act on the parasite as well as the host to control differentiation, reactivation, and host immune control of infection. These studies address significant current gaps in knowledge that are major barriers to progress in the field.

弓形虫（Toxoplasma gondii）引起急性感染，其特征是复制速殖子，最终发展成慢性感染，其特征是持续存在缓殖子阶段弓形虫包囊大脑和中枢神经系统。慢性弓形虫感染影响美国约 30% 的地区人群和免疫缺陷期间包囊重新激活并引起严重的弓形虫脑炎。那里目前没有药物或疗法可以有效预防囊肿发展或消除囊肿慢性感染者。弓形虫包囊发育、再激活和宿主的生物学基础急性和慢性感染的免疫控制仍然知之甚少。从目前的证据和初步根据数据，我们假设铁的可用性调节寄生虫分化、包囊再激活和 CD8+ T 细胞免疫反应在控制急性感染和预防囊肿方面的有效性重新激活。在目标 1 中，我们将研究弓形虫铁调节蛋白对铁感应的作用分化和囊肿再激活。在目标 2 中，我们将研究铁的可用性在发展中的作用 CD8+ T 细胞介导的免疫以及 CD8+ T 细胞对慢性囊肿的控制。这两个具体目标将检验我们的新假设，即铁调节寄生虫阶段分化和宿主对急性和慢性疾病的免疫力。慢性感染。这些高影响力的实验有望定义关键的铁调节机制作用于寄生虫和宿主，控制寄生虫的分化、再激活和宿主免疫控制感染。这些研究解决了当前知识方面的重大差距，这些差距是阻碍科学进步的主要障碍。领域。