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.

项目摘要/摘要 弓形虫Gondii是一种机会性的原生动物病原体，在人类，家畜， 牲畜和野生动植物。该寄生虫以触发强烈炎症免疫反应的能力而闻名 这有效地保护宿主免受感染，但有时可能会导致严重 免疫介导的组织损伤。该提议的长期目标是了解 先天性和获得的免疫反应，可防止与T. gondii和其他微生物感染 病原体。我们在感染小鼠模型中的初步数据揭示了早期T细胞免疫的各个方面 尽管过去数十年的研究已经进行了数十年的研究，但以前尚未得到认可的毒品。感染 CPS1-1是一种通常复制缺陷的毒品菌株，引起了早期保护性CD4+和CD8+ T细胞 响应既不需要IL-12也不需要类似Toll的受体适配器MyD88，仅部分涉及IFN-G， 这对于防止这种寄生虫菌株的行为至关重要。项目的目标 是要了解这些T细胞在防止弓形虫的保护中的功能。中心假设 推动研究的是，感染引起的T细胞表现出新的激活机制 微生物功能。三个具体目标将评估该假设。目标1：确定CPS1-1-是否是否 诱导的T淋巴细胞在常规或非常规抗原特异性的MHC限制性 方式。我们将采用收养转移方法来确定寄生虫诱导的T细胞是否在经典中起作用 MHC I类和MHC II类的限制方式涉及同源抗原。目标2：确定 CPS1-1诱导的CD4+和CD8+ T淋巴细胞的转录组谱和激活表型。 RNA-seq 将用于识别保护细胞所必需的细胞所显示的基本属性。目标3：识别 控制CPS1-1感染的效应器机制。我们将确定两个T细胞介质CD154和 perforin，与IFN-G一起使用采用转移方法以及基因敲除控制感染 老鼠。这项研究的重要性是，我们将揭示以前未被认可的免疫方面 到弓形虫。可以期望这会影响我们的理解，并最终影响感染的能力 弓形虫和其他微生物病原体。