权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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.

项目总结和摘要每年，肝病在全球造成近200万人死亡。肝脏中的免疫反应必须平衡消除局部感染与对良性肠道来源的饮食和微生物抗原的非反应性。在没有感染的情况下，过度/失调的免疫激活促进肝组织损伤，免疫力不足会助长慢性感染和肝细胞癌的发展。因此迫切需要确定可以修改以控制肝脏疾病的免疫途径，危及肝功能我们的建议将利用疟疾肝期感染作为一个模型系统，以确定决定肝脏CD 8 T细胞应答质量的因素。疟原虫疟疾寄生虫最初感染肝脏并作为肝细胞内的肝脏阶段复制，以产生红细胞外裂殖子，感染红细胞肝脏分期对确定感染至关重要，但临床上无症状，最近被证明可以诱导显著的先天免疫反应。我们之前证明了疟原虫感染诱导的IFN-I信号转导通过促进功能失调的肝脏CD 8 T细胞。这种功能失调的特征与T细胞衰竭有着惊人的相似之处，慢性感染和肿瘤引起的程序。然而，一个短暂的，非慢性的感染，导致如此严重的T细胞功能障碍我们现在报道IFN-1信号仅在肝细胞中是诱导肝脏CD 8 T细胞功能障碍的主要因素，表明肝细胞是中枢免疫平台决定肝脏中适应性免疫的质量。从功能测定和基因从感染啮齿类疟原虫或人肝的小鼠富集的肝细胞的表达分析在感染恶性疟原虫的嵌合体小鼠中，我们发现这种IFN-Ⅰ应答是由肝细胞启动的， IRF 3转录因子的表达。此外，我们建立了与IFN-I诱导同时，LS 感染深刻地重塑了肝细胞转录组和代谢组，免疫抑制微环境周围的感染肝细胞，我们预测损害随后的肝T细胞反应。在目标1中，我们将使用尖端的单细胞多组学研究和功能分析，鉴定疟原虫感染诱导的CD 8 T细胞功能障碍的标志性特征，以确定其是否是与真正的T细胞耗竭不同在目标2中，我们将重点关注肝细胞，以表征寄生虫- 诱导的IFN-I信号转导重塑肝细胞内转录组和代谢组以损害肝CD 8 T细胞应答在目标3中，我们将产生新的转基因寄生虫，其将IRF 3的病毒拮抗剂递送到宿主细胞中。感染的肝细胞以仅在感染的肝细胞内损害疟原虫诱导的IFN-I信号传导提高抗疟原虫的适应性免疫力。这些目标将扩大和加深我们对针对复杂真核病原体的免疫应答，以改进肝定向抗疟疾疫苗。