Impairment of anti-Plasmodium T cell memory by type I Interferon Signaling

I 型干扰素信号传导损害抗疟原虫 T 细胞记忆

基本信息

批准号：
10735305
负责人：
Nana Kwaku Minkah
金额：
$ 81.77万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735305
关键词：
Ablation Animals Antigen Presentation Antigens Antimalarials Attenuated Benign Biological Assay Biological Models Bite CD8-Positive T-Lymphocytes Cell Separation Cells Cessation of life Clinical Complex Culicidae Cytoplasm Data Data Set Deposition Development Environment Equilibrium Erythrocytes Exhibits Focal Infection Functional disorder Gene Expression Profiling Hepatic Hepatocyte Human IRF3 gene Immune Immune System Diseases Immune response Immune signaling Immunity Immunize Immunologics Impairment Individual Infection Innate Immune Response Interferon Type I Lipids Liver Liver diseases Malaria Malaria Vaccines Mediating Memory Metabolism Modeling Molecular Molecular Analysis Mus Nutrient Nutrient availability Parasites Parasitic infection Pathway interactions Phenocopy Plasmodium Plasmodium falciparum Play Primary carcinoma of the liver cells Publishing Reporting Rodent Role Shapes Signal Induction Signal Transduction Skin Sporozoites Supplementation T cell response T memory cell T-Lymphocyte Testing Time Tissues Transgenic Organisms Travel Up-Regulation Vaccines Viral Work adaptive immunity amino acid metabolism antagonist chronic infection cytokine dietary exhaust exhaustion human subject immune activation immunoregulation improved in vivo liver function liver infection malaria infection metabolome metabolomics microorganism antigen mouse model multiple omics novel pathogen prevent programmed cell death protein 1 programs receptor response transcription factor transcriptome transcriptomics tumor tumor microenvironment tumor-immune system interactions vaccine efficacy

Ablation Animals Antigen Presentation Antigens Antimalarials Attenuated Benign Biological Assay Biological Models Bite CD8-Positive T-Lymphocytes Cell Separation Cells Cessation of life Clinical Complex Culicidae Cytoplasm Data Data Set Deposition Development Environment Equilibrium Erythrocytes Exhibits Focal Infection Functional disorder Gene Expression Profiling Hepatic Hepatocyte Human IRF3 gene Immune Immune System Diseases Immune response Immune signaling Immunity Immunize Immunologics Impairment Individual Infection Innate Immune Response Interferon Type I Lipids Liver Liver diseases Malaria Malaria Vaccines Mediating Memory Metabolism Modeling Molecular Molecular Analysis Mus Nutrient Nutrient availability Parasites Parasitic infection Pathway interactions Phenocopy Plasmodium Plasmodium falciparum Play Primary carcinoma of the liver cells Publishing Reporting Rodent Role Shapes Signal Induction Signal Transduction Skin Sporozoites Supplementation T cell response T memory cell T-Lymphocyte Testing Time Tissues Transgenic Organisms Travel Up-Regulation Vaccines Viral Work adaptive immunity amino acid metabolism antagonist chronic infection cytokine dietary exhaust exhaustion human subject immune activation immunoregulation improved in vivo liver function liver infection malaria infection metabolome metabolomics microorganism antigen mouse model multiple omics novel pathogen prevent programmed cell death protein 1 programs receptor response transcription factor transcriptome transcriptomics tumor tumor microenvironment tumor-immune system interactions vaccine efficacy

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项目摘要

PROJECT SUMMARY AND ABSTRACT Annually, liver disease accounts for nearly 2 million deaths worldwide. Immune responses in the liver must balance elimination of local infection with non-reactivity to benign gut-derived dietary and microbial antigens. Excessive/dysregulated immune activation in the absence of infection promotes liver tissue damage while insufficient immunity facilitates the development of chronic infection and hepatocellular carcinoma. Thus, there is an urgent need to pinpoint immunological pathways that can be modified to control hepatic maladies without compromising liver function. Our proposal will utilize malaria liver stage infection as a model system to identify factors that dictate the quality of hepatic CD8 T cell responses. Plasmodium malaria parasites initially infect the liver and replicate as liver stages within hepatocytes to generate exoerythrocytic merozoites that are released to infect red blood cells. Liver stages are essential to establish infection but are clinically silent and were only recently shown to induce a significant innate immune response. We previously demonstrated that Plasmodium infection induced IFN-I signaling weakens anti-Plasmodium adaptive immunity by promoting the development of dysfunctional hepatic CD8 T cells. This dysfunctional signature bears striking similarity to the T cell exhaustion program induced by chronic infection and tumors. Yet, how does a transient, non-chronic infection that is limited to hepatocytes induce such profound T cell dysfunction? We now report that IFN-I signaling solely in hepatocytes is a major contributor to the induction of hepatic CD8 T cell dysfunction suggesting that hepatocytes are central immune platforms that determine the quality of adaptive immunity in the liver. From functional assays and gene expression analyses of hepatocytes enriched from mice infected with rodent malaria parasites or human-liver chimeric mice infected with Plasmodium falciparum, we show that this IFN-I response is initiated by hepatocyte expression of the IRF3 transcription factor. Moreover, we establish that concurrent with IFN-I induction, LS infection profoundly reshapes the hepatocyte transcriptome and metabolome likely inducing an immunosuppressive microenvironment around the infected hepatocyte, which we predict impairs an ensuing hepatic T cell response. In Aim 1, we will use cutting-edge single cell multi-omic studies and functional analyses to identify hallmark features of Plasmodium infection induced CD8 T cell dysfunction to determine whether it is distinct from bonafide T cell exhaustion. In Aim 2, we will focus on hepatocytes to characterize how parasite- induced IFN-I signaling remodels intrahepatocyte transcriptomes and metabolomes to impair hepatic CD8 T cell responses. In Aim 3, we will generate novel transgenic parasites that deliver viral antagonists of IRF3 into the infected hepatocyte to compromise Plasmodium-induced IFN-I signaling solely within the infected hepatocyte and improve anti-Plasmodium adaptive immunity. These aims will broaden and deepen our understanding of the immune responses to a complex eukaryotic pathogen to improve liver-directed anti-malaria vaccines.

项目摘要和摘要每年，肝病在全球范围内造成近200万人死亡。肝脏中的免疫反应必须平衡消除局部感染，对良性肠源性饮食和微生物抗原的无反应性。在没有感染的情况下，过度/失调的免疫激活会促进肝组织损伤，而免疫力不足可促进慢性感染和肝细胞癌的发展。因此，那里迫切需要查明可以修改以控制肝病的免疫途径损害肝功能。我们的建议将利用疟疾肝阶段感染作为模型系统来识别决定肝CD8 T细胞反应质量的因素。疟原虫寄生虫最初感染肝细胞内的肝脏阶段复制并复制，以产生释放到感染红细胞。肝脏阶段对于建立感染至关重要，但在临床上保持沉默，只是最近证明可以引起明显的先天免疫反应。我们先前证明了疟原虫感染引起的IFN-I信号传导通过促进的发展而削弱了抗质量自适应免疫功能失调的肝CD8 T细胞。这种功能失调的签名与T细胞耗尽相似慢性感染和肿瘤引起的程序。但是，瞬态，非少气感染如何受到限制肝细胞会诱导如此深刻的T细胞功能障碍？我们现在报告说，IFN-I仅在肝细胞中发出信号是诱导肝CD8 T细胞功能障碍的主要因素，这表明肝细胞是中心的确定肝脏自适应免疫质量的免疫平台。来自功能分析和基因来自感染啮齿动物疟原虫或人肝脏的小鼠的肝细胞的表达分析感染了恶性疟原虫的嵌合小鼠，我们表明这种IFN-I反应是由肝细胞引发的 IRF3转录因子的表达。此外，我们确定了与IFN-I诱导同时发生的感染深刻重塑了肝细胞转录组和代谢组可能诱导受感染的肝细胞周围的免疫抑制微环境，我们预测这会损害随后的肝T细胞反应。在AIM 1中，我们将使用尖端的单细胞多词研究和功能分析识别疟原虫感染的标志性特征诱导CD8 T细胞功能障碍以确定它是否是与真正的T细胞耗尽不同。在AIM 2中，我们将专注于肝细胞，以表征寄生虫如何诱导的IFN-I信号转导重塑了epatocyte的转录组和代谢组，以损害肝CD8 T细胞回答。在AIM 3中，我们将产生新型的转基因寄生虫，这些寄生虫将IRF3的病毒拮抗剂传递到感染的肝细胞仅在感染的肝细胞中损害疟原虫诱导的IFN-I信号传导并改善抗质量自适应免疫。这些目标将扩大和加深我们对对复杂的真核病原体的免疫反应，以改善肝脏指导的抗马拉里亚疫苗。