CD4 dysfunction and cerebral toxoplasmosis

CD4功能障碍与脑弓形体病

基本信息

批准号：
10403626
负责人：
IMTIAZ AHMED KHAN
金额：
$ 59.82万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403626
关键词：
Ablation Acquired Immunodeficiency Syndrome Agonist Antigens Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Maintenance Cell physiology Cells Central Nervous System Infections Cerebral Toxoplasmosis Chromatin Chronic Communicable Diseases Data Development Down-Regulation Economics Encephalitis Epigenetic Process Exhibits Failure Food Functional disorder Goals HIV Infections Human Immunity Immunocompromised Host Individual Infection Laboratories Life Link Maintenance Malignant Neoplasms Mediating Memory Methylation Mus OX40 Parasites Patients Play Population Predisposition Publishing Receptor Gene Recovery Reporting Role Signal Transduction Signaling Molecule Site T cell response Therapeutic Therapeutic Agents Toxoplasma Toxoplasma gondii Toxoplasmosis United States Up-Regulation chronic infection cytotoxic exhaustion experimental study insight latent infection mouse model pathogen prevent programs promoter reactivation from latency receptor response restoration toxoplasmic encephalitis transcription factor

项目摘要

Abstract Latent toxoplasmosis continues to be a problem for immunocompromised infected individuals and toxoplasmic encephalitis (TE) is one of the most common life threatening central nervous system infections in these patients. The reactivation of latent toxoplasmosis is attributed to lack of adequate CD4 T cell help that compromises the CD8 T cell immunity against the parasite. Similar to humans, mouse models of toxoplasmosis have demonstrated the critical role of CD4 T cells for the maintenance of robust CD8 T cell immunity. In a 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, which causes an increase in the expression of inhibitory receptors on these cells. Preliminary data for the proposal suggests that during latent toxoplasmosis increased BLIMP-1 expression leads to epigenetic changes in antigen-specific, CD4 TCM (central memory) subset. The transcription factor gains accessibility to chromatin sites on this population and changes their epigenetic landscape. BLIMP-1 ablation re-invigorates CD4 T cells due to downregulation of inhibitory receptors and increased expression of positive co-stimulatory molecules. The proposal has two specific aims. In aim 1 we will determine the chromatin accessible sites on CD4 TCM that BLIMP-1 binds to. We plan to define the epigenetic changes in CD4 TCM during latent toxoplasmosis that leads to their exhaustion. In aim 2 studies will be performed to evaluate if restoration of CD4 T cell function due to BLIMP-1 ablation is dependent on the up-regulation of 4-1BB and OX40 or other costimulatory molecules identified in aim 1. We will determine if cell intrinsic signaling by these co- stimulatory molecules is required for optimal recovery of CD4 T cell function in BLIMP-1 ablated cells. Finally, studies will be performed to determine if CD4 T cells treated with agonist for co-stimulatory molecules downregulate inhibitory receptors on CD8 population and confer strong effector cytotoxic program on these cells that is critical for containing chronic toxoplasma infection.

抽象的潜伏性弓形体病仍然是免疫功能低下感染者的一个问题弓形虫脑炎 (TE) 是最常见的危及生命的疾病之一这些患者的中枢神经系统感染。潜在的重新激活弓形虫病是由于缺乏足够的 CD4 T 细胞帮助而损害 CD8 T 细胞对寄生虫具有免疫力。与人类类似，弓形虫病小鼠模型已经证明 CD4 T 细胞对于维持强大的 CD8 T 的关键作用细胞免疫。在最近的一项研究中，我们证明 CD8 T 功能障碍会导致慢性感染宿主的重新激活是 CD4 T 细胞耗尽的结果。用抗原特异性未耗尽的 CD4 T 细胞治疗慢性宿主可以恢复 CD8 T 细胞功能并防止重新激活。有趣的是，CD4 耗尽是相关的转录因子 BLIMP-1 的上调，导致这些细胞上抑制性受体的表达。提案的初步数据表明在潜伏性弓形虫病期间，BLIMP-1 表达增加会导致抗原特异性 CD4 TCM（中央记忆）子集的表观遗传变化。这转录因子获得了对该群体染色质位点的可及性并发生变化他们的表观遗传景观。 BLIMP-1 消融可重新激活 CD4 T 细胞，因为抑制性受体的下调和正性共刺激的表达增加分子。该提案有两个具体目标。在目标 1 中，我们将确定染色质 BLIMP-1 结合的 CD4 TCM 上的可访问位点。我们计划定义表观遗传潜伏性弓形虫病期间 CD4 TCM 发生变化，导致其衰竭。目标2 将进行研究以评估 BLIMP-1 是否能恢复 CD4 T 细胞功能消融取决于 4-1BB 和 OX40 或其他共刺激的上调目标 1 中确定的分子。我们将确定这些共同作用的细胞内在信号传导是否 BLIMP-1 中 CD4 T 细胞功能的最佳恢复需要刺激分子消融的细胞。最后，将进行研究以确定 CD4 T 细胞是否用共刺激分子激动剂下调 CD8 群体的抑制性受体并赋予这些细胞强大的效应细胞毒性程序，这对于包含慢性弓形虫感染。