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:
- 金额:$ 28.43万
- 依托单位:
- 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:
- 关键词:AcuteAntibodiesAntiviral AgentsBacteriaBacterial InfectionsBiologicalCD4 Positive T LymphocytesCD8B1 geneCancer VaccinesCellsCharacteristicsClinicalCodeComplexCross PresentationCross-PrimingDataDendritic CellsDiseaseEnterovirusEpitopesGoalsGrantHumanImmuneImmune responseImmunityImmunologyIn VitroInfectionInjection of therapeutic agentMHC Class I GenesMediator of activation proteinMessenger RNAMicrobeMusNamesNatureOrganismPaperPathway interactionsPeptidesPlayProcessProteinsRNAReadingRecombinantsRegulatory ElementRoleSignal TransductionStudy SectionSurfaceT cell responseT-LymphocyteTestingTransfer RNATranslatingTranslationsUncertaintyVaccinationVaccinesViralViral ProteinsVirusVirus DiseasesWorkYeastscell typeextracellularhigh rewardhigh riskin vivoinnovationmicrobialpathogenpublic health relevanceresearch studytumorvector 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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J. Lindsay Whitton其他文献
Host and virus determinants of picornavirus pathogenesis and tropism
小核糖核酸病毒发病机制和嗜性的宿主和病毒决定因素
- DOI:
10.1038/nrmicro1284 - 发表时间:
2005-10-01 - 期刊:
- 影响因子:103.300
- 作者:
J. Lindsay Whitton;Christopher T. Cornell;Ralph Feuer - 通讯作者:
Ralph Feuer
Microorganisms and autoimmunity: making the barren field fertile?
微生物与自身免疫:让贫瘠的领域肥沃起来?
- DOI:
10.1038/nrmicro754 - 发表时间:
2003-11-01 - 期刊:
- 影响因子:103.300
- 作者:
Matthias G. von Herrath;Robert S. Fujinami;J. Lindsay Whitton - 通讯作者:
J. Lindsay Whitton
J. Lindsay Whitton的其他文献
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{{ truncateString('J. Lindsay Whitton', 18)}}的其他基金
Coxsackieviral pancreatitis: autophagy, proteolysis, and inflammation
柯萨奇病毒性胰腺炎:自噬、蛋白水解和炎症
- 批准号:
9225171 - 财政年份:2015
- 资助金额:
$ 28.43万 - 项目类别:
Coxsackieviral pancreatitis: autophagy, proteolysis, and inflammation
柯萨奇病毒性胰腺炎:自噬、蛋白水解和炎症
- 批准号:
9027796 - 财政年份:2015
- 资助金额:
$ 28.43万 - 项目类别:
Coxsackieviral pancreatitis: autophagy, proteolysis, and inflammation
柯萨奇病毒性胰腺炎:自噬、蛋白水解和炎症
- 批准号:
8795589 - 财政年份:2015
- 资助金额:
$ 28.43万 - 项目类别:
Analyzing the effects of type I interferons in the enterovirus-infected heart
分析 I 型干扰素对肠道病毒感染心脏的影响
- 批准号:
9198190 - 财政年份:2015
- 资助金额:
$ 28.43万 - 项目类别:
Analyzing the effects of type I interferons in the enterovirus-infected heart
分析 I 型干扰素对肠道病毒感染心脏的影响
- 批准号:
8997975 - 财政年份:2015
- 资助金额:
$ 28.43万 - 项目类别:
How do enteroviruses almost completely evade the attentions of CD8+ T cells?
肠道病毒是如何几乎完全逃避CD8 T细胞的注意的?
- 批准号:
8811097 - 财政年份:2014
- 资助金额:
$ 28.43万 - 项目类别:
How do enteroviruses almost completely evade the attentions of CD8+ T cells?
肠道病毒是如何几乎完全逃避CD8 T细胞的注意的?
- 批准号:
8630094 - 财政年份:2014
- 资助金额:
$ 28.43万 - 项目类别:
mRNA as a mediator of immunological information transfer in vivo
mRNA 作为体内免疫信息传递的介质
- 批准号:
8854024 - 财政年份:2014
- 资助金额:
$ 28.43万 - 项目类别:
mRNA as a mediator of immunological information transfer in vivo
mRNA 作为体内免疫信息传递的介质
- 批准号:
8894191 - 财政年份:2014
- 资助金额:
$ 28.43万 - 项目类别:
Cytotoxic T Cell Responses to Virus Infection
细胞毒性 T 细胞对病毒感染的反应
- 批准号:
8524204 - 财政年份:2012
- 资助金额:
$ 28.43万 - 项目类别:
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