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

• 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
• 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

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，全球有近200万人死于肝病。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 免疫不足导致慢性感染和肝细胞癌的发生。因此，在那里 迫切需要确定免疫途径，这些免疫途径可以被修改以控制肝病，而不需要 损害了肝功能。我们的建议将利用疟疾肝期感染作为一个模式系统来识别 决定肝脏CD8 T细胞反应质量的因素。疟疾寄生虫最初感染 并在肝细胞内复制为肝期以产生红外型裂殖子，这些裂殖子释放到 感染红血球。肝脏分期是确定感染的关键，但在临床上是沉默的，只有 最近被证明能诱导显著的先天免疫反应。我们之前证明了疟原虫 感染诱导的干扰素-I信号通过促进疟疾的发展而削弱抗疟原虫获得性免疫 肝脏CD8 T细胞功能紊乱。这种功能失调的特征与T细胞衰竭有着惊人的相似之处 由慢性感染和肿瘤引起的程序。然而，一种短暂的、非慢性的有限感染 肝细胞会导致如此严重的T细胞功能障碍？我们现在报道，干扰素-I信号只在肝细胞中 是导致肝脏CD8 T细胞功能障碍的主要因素，提示肝细胞是中枢 决定肝脏适应性免疫质量的免疫平台。从功能分析和基因 鼠疟原虫或人肝感染小鼠肝细胞的表达分析 感染恶性疟原虫的嵌合小鼠，我们证明了这种干扰素-I反应是由肝细胞启动的 IRF3转录因子的表达。此外，我们建立了与干扰素-I诱导同时进行的LS 感染深刻地重塑了肝细胞转录组和代谢组，可能导致 感染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。在目标1中，我们将使用尖端的单细胞多组体研究和功能分析 鉴定疟原虫感染所致CD8 T细胞功能障碍的特征以确定其是否 有别于真正的T细胞衰竭。在目标2中，我们将重点研究肝细胞，以确定寄生虫是如何- 诱导的干扰素-I信号重塑肝细胞内转录和代谢产物以损伤肝脏CD8 T细胞 回应。在目标3中，我们将产生新型的转基因寄生虫，将IRF3的病毒拮抗剂输送到 感染肝细胞仅在感染肝细胞内破坏疟原虫诱导的干扰素-I信号 提高抗疟原虫获得性免疫。这些目标将扩大和加深我们对 对一种复杂真核病原体的免疫反应，以改进肝脏导向的抗疟疾疫苗。