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mRNA as a mediator of immunological information transfer in vivo

mRNA 作为体内免疫信息传递的介质

基本信息

批准号：
8735569
负责人：
J. Lindsay Whitton
金额：
$ 28.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8735569
关键词：
Acute Antibodies Antiviral Agents Bacteria Bacterial Infections Biological CD4 Positive T Lymphocytes CD8B1 gene Cancer Vaccines Cells Characteristics Clinical Code Complex Cross Presentation Cross-Priming Data Dendritic Cells Disease Enterovirus Epitopes Goals Grant Human Immune Immune response Immunity Immunology In Vitro Infection Injection of therapeutic agent MHC Class I Genes Mediator of activation protein Messenger RNA Microbe Mus Names Nature Organism Paper Pathway interactions Peptides Play Process Proteins RNA Reading Recombinants Regulatory Element Role Signal Transduction Study Section Surface T cell response T-Lymphocyte Testing Transfer RNA Translating Translations Uncertainty Vaccination Vaccines Viral Viral Proteins Virus Virus Diseases Work Yeasts cell type extracellular high reward high risk in vivo innovation microbial pathogen public health relevance research study tumor vector vaccine

项目摘要

In vivo injection of mRNA triggers immune responses to the encoded proteins, and confers protection against disease. For this and other reasons, outlined below, RNA vaccines have great clinical potential, so it is important that we understand how they induce immunity. I hypothesize that RNA vaccines may be exploiting a cell type, and biological pathway, that have evolved specifically to capture, internalize, and translate mRNA. I propose that this pathway facilitates the transfer of immunological information into uninfected dendritic cells (DCs), thereby playing a key part in regulating CD8+ T cell responses to many viral and bacterial infections. Almost all acute virus infections induce strong CD8+ T cell responses, which are initiated when na¿ve CD8+ T cells are activated by contact with an MHC class I / epitope peptide complex on the surface of DCs that express appropriate costimulatory molecules. However, many viruses do not infect DCs; and some viruses that infect DCs also encode proteins that quite effectively inhibit MHC class I presentation. These facts posed a puzzle: how could epitopes encoded by these viruses be effectively presented by DCs? The answer came with the identification of cross-presentation which, if it results in the triggering of naive CD8+ T cells, causes cross-priming. However, two in vivo observations show that cross-presentation/cross-priming (hereinafter, CP) is not always highly-efficient. First, enteroviruses replicate to very high titers and induce CD4+ T cells and antibodies, yet (unique among acute virus infections) they completely avoid triggering na¿ve CD8+ T cells. Second, extracellular bacterial infections, in which microbial protein is hugely abundant, do not induce strong CD8+ T cell responses. For reasons described below, I hypothesize that both observations can be explained by proposing that some transfer of immunological information into uninfected DCs may rely on mRNA (rather than protein). So, this proposal has two goals: First, to evaluate how naked RNA induces immunity. Second, to test the hypothesis that, during most microbial infections, mRNA is transferred to uninfected DCs; if it is translated therein, the encoded protein will reach the class I MHC pathway, inducing strong CD8+ T cell responses; I have named this mechanism TATOR (transfer and translation of RNA). Conversely, if the mRNA cannot be translated, the organism is undetectable by CD8+ T cells. Thus, the specific characteristics of their mRNAs renders enteroviruses and extracellular bacteria invisible to CD8+ T cells. Aim 1. To identify and characterize the DC subset that is involved in RNA-triggered immunity. Aim 2. To determine if mRNA regulatory sequences explain why extracellular bacteria fail to induce strong CD8+ T cell responses.

体内注射mRNA可触发对编码蛋白的免疫应答，并赋予保护作用。对抗疾病由于这个原因和下文概述的其他原因，RNA疫苗具有巨大的临床潜力，所以我们必须了解它们是如何诱导免疫的。我假设RNA疫苗可能利用一种细胞类型和生物学途径，它们已经进化到专门捕获，内化，翻译mRNA。我认为这条通路促进了免疫信息的传递，未感染的树突状细胞（DC），从而在调节CD 8 + T细胞对许多病毒和细菌感染。几乎所有的急性病毒感染都会诱导强烈的CD 8 + T细胞应答，当幼稚CD 8 + T细胞通过与MHC I类/表位肽接触而被激活时，复合物的表面上的DC表达适当的共刺激分子。但不少病毒不感染DC;一些感染DC的病毒也编码蛋白质，抑制MHC I类呈递。这些事实提出了一个难题：这些蛋白质编码的表位病毒是否能被DC有效提呈？答案来自于对交叉呈现的识别如果其导致初始CD 8 + T细胞的触发，则引起交叉致敏。然而，两个体内观察表明，交叉呈现/交叉启动（下文称为CP）并不总是高效的。首先，肠道病毒复制到非常高的滴度，并诱导CD 4 + T细胞和抗体，但（独特的在急性病毒感染中），它们完全避免触发幼稚的CD 8 + T细胞。第二，细胞外细菌感染，其中微生物蛋白质是非常丰富的，不诱导强大的CD 8 + T细胞应答由于下面描述的原因，我假设这两个观察结果可以解释为：提出一些免疫信息向未感染的DC的传递可能依赖于mRNA，（而不是蛋白质）所以，这个提议有两个目标：首先，评估裸RNA如何诱导免疫力第二，为了检验这一假设，在大多数微生物感染期间，mRNA被转移到未感染的DC;如果它在其中被翻译，则编码的蛋白质将到达I类MHC途径，诱导强烈的CD 8 + T细胞反应;我将这种机制命名为TATOR（转移和翻译 RNA）。相反，如果mRNA不能被翻译，则生物体不能被CD 8 + T细胞检测到。因此，其mRNA的特定特征使得肠道病毒和细胞外细菌对CD 8 + T细胞不可见。目标1.鉴定和表征参与RNA触发免疫的DC亚群。目标2.为了确定mRNA调控序列是否能解释细胞外细菌不能诱导强CD 8 + T细胞应答。