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

• 批准号: 10633247
• 负责人: ERIC Y DENKERS
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10633247
• 关键词: Acute; Adoptive Transfer; Animals; Antibodies; Antigens; Automobile Driving; Biological; Biological Response Modifiers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Separation; Cells; Classification; Color; Cytolysis; Cytoprotection; Data; Dendritic Cells; Discipline; Disease; Domestic Animals; Engineering; Flow Cytometry; Gene Expression Profile; Genes; Goals; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunology; Infection; Infection Control; Infectious Agent; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Knock-out; Knockout Mice; Knowledge; Life; Literature; Livestock; Lymphocyte Function; MAP Kinase Gene; MHC Class I Genes; MHC Class II Genes; Macrophage; Mediating; Mediator; Modeling; Mus; NF-kappa B; Natural Killer Cells; Nature; Opportunistic Infections; Ovalbumin; Parasites; Pathway interactions; Phenotype; Play; Population; Predisposition; Production; Property; Public Health; Research; Resistance; Role; Specificity; T cell response; T-Lymphocyte; TNFSF5 gene; Tissues; Toll-like receptors; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Uracil; Vaccines; Virulent; Western Blotting; Work; antimicrobial; biodefense; congenital infection; cytokine; differential expression; disorder control; improved; in vivo Model; insight; knockout gene; microbial; monocyte; mouse model; neutrophil; novel; pathogen; pathogenic microbe; perforin; prevent; profilin; response; transcriptome sequencing; transcriptomics

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 cps 1 -1是一种正常复制缺陷型弓形虫株，可诱导早期保护性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。