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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.

在体内注射mRNA可触发对编码蛋白的免疫反应，并提供保护