New insights into early T cell protection during acute toxoplasmosis
急性弓形虫病期间早期 T 细胞保护的新见解
基本信息
- 批准号:10633247
- 负责人:
- 金额:$ 18.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-02 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdoptive TransferAnimalsAntibodiesAntigensAutomobile DrivingBiologicalBiological Response ModifiersCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell SeparationCellsClassificationColorCytolysisCytoprotectionDataDendritic CellsDisciplineDiseaseDomestic AnimalsEngineeringFlow CytometryGene Expression ProfileGenesGoalsHumanImmuneImmune responseImmunityImmunocompromised HostImmunologyInfectionInfection ControlInfectious AgentInflammationInflammatoryInterferon Type IIInterleukin-12Knock-outKnockout MiceKnowledgeLifeLiteratureLivestockLymphocyte FunctionMAP Kinase GeneMHC Class I GenesMHC Class II GenesMacrophageMediatingMediatorModelingMusNF-kappa BNatural Killer CellsNatureOpportunistic InfectionsOvalbuminParasitesPathway interactionsPhenotypePlayPopulationPredispositionProductionPropertyPublic HealthResearchResistanceRoleSpecificityT cell responseT-LymphocyteTNFSF5 geneTissuesToll-like receptorsToxoplasmaToxoplasma gondiiToxoplasmosisUracilVaccinesVirulentWestern BlottingWorkantimicrobialbiodefensecongenital infectioncytokinedifferential expressiondisorder controlimprovedin vivo Modelinsightknockout genemicrobialmonocytemouse modelneutrophilnovelpathogenpathogenic microbeperforinpreventprofilinresponsetranscriptome sequencingtranscriptomics
项目摘要
Project Summary/Abstract
Toxoplasma gondii is an opportunistic protozoan pathogen widespread in humans, domestic animals,
livestock and wildlife. The parasite is known for its ability to trigger a strong inflammatory immune response
that is effective in protecting the host from infection, but that can nonetheless sometimes cause severe
immune-mediated tissue damage. The long-term objective of this proposal is to understand the basis of
innate and acquired immune responses that protect against infection with T. gondii and other microbial
pathogens. Our preliminary data in mouse models of infection reveal aspects of early T cell immunity to
Toxoplasma that have not previously been recognized, despite many decades of past research. Infection with
cps1-1, a normally replication-defective Toxoplasma strain, elicits an early protective CD4+ and CD8+ T cell
response that requires neither IL-12 nor Toll-like receptor adaptor MyD88, that only partially involves IFN-g,
and that is essential to prevent this parasite strain from behaving in a virulent manner. The goal of the project
is to understand the function of these T cells in protection against Toxoplasma. The central hypothesis
driving the research is that the T cells elicited by infection display novel mechanisms of activation and anti-
microbial function. Three specific aims will evaluate the hypothesis. Aim 1: Determine whether cps1-1-
induced T lymphocytes function in a conventional or nonconventional antigen-specific, MHC-restricted
manner. We will employ adoptive transfer approaches to determine if parasite-induced T cells act in a classical
MHC class I and MHC class II restricted manner involving cognate antigen. Aim 2: Determine the
transcriptomic profile and activation phenotype of cps1-1-induced CD4+ and CD8+ T lymphocytes. RNA-seq
will be used to identify the underlying properties displayed by the cells necessary for protection. Aim 3: Identify
effector mechanisms controlling cps1-1 infection. We will determine how two T cell mediators, CD154 and
perforin, act with IFN-g to control infection employing an adoptive transfer approach along with gene knockout
mice. The importance of this research is that we stand to reveal previously unrecognized aspects of immunity
to Toxoplasma. This can be expected to impact our understanding and ultimately ability to treat infection with
Toxoplasma and other microbial pathogens.
项目总结/摘要
弓形虫是一种广泛存在于人类、家畜
牲畜和野生动物。这种寄生虫以其引发强烈炎症免疫反应的能力而闻名
这是有效地保护宿主免受感染,但有时也会导致严重的
免疫介导的组织损伤。本提案的长期目标是了解
先天性和获得性免疫反应,保护免受T.弓形虫和其他微生物
病原体我们在小鼠感染模型中的初步数据揭示了早期T细胞免疫的各个方面,
弓形虫以前没有被承认,尽管过去几十年的研究。感染
正常复制缺陷型弓形虫株cps 1 -1诱导早期保护性CD 4+和CD 8 + T细胞
应答既不需要IL-12也不需要Toll样受体接头MyD 88,仅部分涉及IFN-γ,
这对于防止这种寄生虫株以毒性方式表现是必不可少的。该项目的目标
就是了解这些T细胞在抵御弓形虫中的功能。核心假设
推动这项研究的是,感染引起的T细胞显示出激活和抗-
微生物功能三个具体目标将评估该假设。目标1:确定cps 1 -1-
诱导的T淋巴细胞在常规或非常规抗原特异性、MHC限制性
方式我们将采用过继转移方法来确定寄生虫诱导的T细胞是否在经典的免疫应答中起作用。
涉及同源抗原的MHC I类和MHC II类限制性方式。目标2:确定
cps 1 -1诱导的CD 4+和CD 8 + T淋巴细胞的转录组学特征和活化表型。RNA-seq
将用于识别保护所需的单元格所显示的基本属性。目标3:确定
控制CPS 1 -1感染的效应器机制。我们将确定两种T细胞介质,CD 154和
穿孔素,与IFN-γ一起使用过继转移方法连同基因敲除沿着来控制感染
小鼠这项研究的重要性在于我们揭示了以前未被认识的免疫方面
弓形虫这可能会影响我们对感染的理解和最终治疗感染的能力。
弓形虫和其他微生物病原体。
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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{{ truncateString('ERIC Y DENKERS', 18)}}的其他基金
MyD88-independent resistance to Toxoplasma in the intestine
MyD88 独立的肠道内对弓形虫的抵抗力
- 批准号:
10393513 - 财政年份:2018
- 资助金额:
$ 18.66万 - 项目类别:
MyD88-independent resistance to Toxoplasma in the intestine
MyD88 独立的肠道内弓形虫抵抗力
- 批准号:
9915889 - 财政年份:2018
- 资助金额:
$ 18.66万 - 项目类别:
Unravelling MyD88-dependent and independent mucosal immunity to Toxoplasma
揭示 MyD88 依赖性和独立的弓形虫粘膜免疫
- 批准号:
10735738 - 财政年份:2018
- 资助金额:
$ 18.66万 - 项目类别:
Basis of MyD88-independent Th1 immunity during Toxoplasma infection
弓形虫感染期间不依赖 MyD88 的 Th1 免疫的基础
- 批准号:
9110482 - 财政年份:2016
- 资助金额:
$ 18.66万 - 项目类别:
Basis of MyD88-independent Th1 immunity during Toxoplasma infection
弓形虫感染期间不依赖 MyD88 的 Th1 免疫的基础
- 批准号:
9267461 - 财政年份:2016
- 资助金额:
$ 18.66万 - 项目类别:
Role of DC Wnt/beta-catenin signaling in Toxoplasma infection
DC Wnt/β-连环蛋白信号在弓形虫感染中的作用
- 批准号:
8619823 - 财政年份:2013
- 资助金额:
$ 18.66万 - 项目类别:
Role of intraepithelial T cells in Toxoplasma gondii-induced inflammatory ileitis
上皮内 T 细胞在弓形虫诱发的炎症性回肠炎中的作用
- 批准号:
7870442 - 财政年份:2009
- 资助金额:
$ 18.66万 - 项目类别:
Role of intraepithelial T cells in Toxoplasma gondii-induced inflammatory ileitis
上皮内 T 细胞在弓形虫诱发的炎症性回肠炎中的作用
- 批准号:
7706691 - 财政年份:2009
- 资助金额:
$ 18.66万 - 项目类别:
Role of CCL2/MCP-1 in mucosal immunity to Toxoplasma
CCL2/MCP-1在弓形虫粘膜免疫中的作用
- 批准号:
7282869 - 财政年份:2007
- 资助金额:
$ 18.66万 - 项目类别:
Role of CCL2/MCP-1 in mucosal immunity to Toxoplasma
CCL2/MCP-1在弓形虫粘膜免疫中的作用
- 批准号:
7475257 - 财政年份:2007
- 资助金额:
$ 18.66万 - 项目类别:
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