miR146a and CD4 dysfunction during chronic toxoplasmosis

慢性弓形虫病期间 miR146a 和 CD4 功能障碍

基本信息

批准号：
9435967
负责人：
IMTIAZ AHMED KHAN
金额：
$ 19.94万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-19 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9435967
关键词：
Animals Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Chronic Country Data Development Disease Economics Encephalitis Exhibits Food Functional disorder Future Generations Goals Human Immunity Immunocompetent Immunocompromised Host Individual Infection Infection Control Journals Laboratories Lead Life Link Maintenance Mediating Medicine Metabolic Metabolic Pathway MicroRNAs Mus Neuraxis Neurologic PRDM1 gene Parasite Control Parasites Pathogenicity Play Pregnancy Publications Publishing Regimen Regulation Reporting Role SLEB2 gene Series T cell response T-Lymphocyte TNF Receptor-Associated Factors TRAF6 gene Therapeutic Toxoplasma Toxoplasma gondii Toxoplasmosis United States Up-Regulation base chronic infection congenital infection design exhaustion experimental study immune system function immunoregulation improved insight latent infection novel overexpression pathogen prevent reactivation from latency transcription factor

项目摘要

Toxoplasmic gondii, an apicomplexan parasite is a pathogenic protozoan that can infect the central nervous system. Infection during pregnancy can result in congenital infection with severe neurological consequences. In immunocompromised individuals reactivation of latent neurological foci can result in encephalitis. Although CD8+ T cells play an important effector role in controlling the chronic infection, their maintenance is dependent on critical help provided by CD4 T cells. In a very recent study we demonstrated that CD8 T dysfunction leading to reactivation in chronically infected host is a consequence of CD4 T cell exhaustion. Treatment of chronic host with antigen- specific non-exhausted CD4 T cells can restore CD8 T cell functionality and prevent reactivation. Interestingly CD4 exhaustion is linked to up-regulation of transcription factor BLIMP-1. In this proposal mechanism responsible for CD4 T cell dysfunction/exhaustion during chronic toxoplasmosis will be interrogated. Preliminary data for the proposal suggests that increased expression of transcription factor BLIMP-1 on CD4 T cells is due to up-regulation of miR146a, which likely is a primary cause of their dysfunction. The proposal has two specific aims. In aim 1 the mechanism responsible for increased BLIMP-1 expression on CD4 T cells will be evaluated. As preliminary data points at the role of miR146a, the studies will be performed to determine if in the absence of miR146a, BLIMP-1 expression can be down-regulated and CD4 T cell exhaustion prevented. Experiments will be performed to determine if over-expression of miR146a on non-exhausted CD4 T cells can lead to their dysfunctionality. Preliminary data for the proposal shows that antigen-specific CD4 T cells from miR146-/- mice express increased TRAF6 as compared to the cells from wild type animals. In aim 2, studies related to novel concept that TRAF6 plays an important role in the regulation of BLIMP-1 on CD4 T cells will be performed. We plan to determine if increased BLIMP-1 expression on CD4 T cells (due to targeting of TRAF6 by miR146a) alters their metabolic pathway.

刚地弓形虫是一种顶复门寄生虫，是一种致病性原生动物，可以感染中枢神经系统。怀孕期间感染可导致先天性感染具有严重的神经系统后果。在免疫功能低下的个体中重新激活潜在的神经病灶可导致脑炎。尽管 CD8+ T 细胞发挥着在控制慢性感染中发挥重要的效应作用，其维持是依赖 CD4 T 细胞提供的关键帮助。在最近的一项研究中，我们证明 CD8 T 功能障碍导致慢性感染宿主重新激活是 CD4 T 细胞耗竭的结果。用抗原治疗慢性宿主特定的未耗尽的 CD4 T 细胞可以恢复 CD8 T 细胞的功能并预防重新激活。有趣的是，CD4 耗竭与转录因子的上调有关飞艇-1。在该提案中，CD4 T 细胞功能障碍/耗竭的机制慢性弓形虫病期间将受到询问。提案的初步数据表明 CD4 T 细胞上转录因子 BLIMP-1 表达增加是由于 miR146a 的上调，这可能是其功能障碍的主要原因。这提案有两个具体目标。在目标 1 中，负责增加的机制将评估 CD4 T 细胞上的 BLIMP-1 表达。作为初步数据点 miR146a 的作用，将进行研究以确定是否在缺乏 miR146a 的情况下 miR146a、BLIMP-1 表达可下调且 CD4 T 细胞耗竭阻止了。将进行实验以确定 miR146a 是否过度表达未耗尽的 CD4 T 细胞会导致其功能障碍。初步数据提案表明来自 miR146-/- 小鼠的抗原特异性 CD4 T 细胞表达与野生型动物的细胞相比，TRAF6 增加。在目标 2 中，研究与 TRAF6 在 BLIMP-1 调节中发挥重要作用的新概念相关将在 CD4 T 细胞上进行。我们计划确定 BLIMP-1 表达是否增加 CD4 T 细胞（由于 miR146a 靶向 TRAF6）改变了它们的代谢途径。