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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.

项目总结与摘要