The role of CD40L in resistance to enteric infection

CD40L在抵抗肠道感染中的作用

• 批准号: 10470882
• 负责人: CHRISTOPHER A HUNTER
• 金额: $ 55.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470882
• 关键词: Address; Affect; Agonist; Antigens; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cell surface; Cells; Cellular Immunology; Child; Chronic; Communities; Cryptosporidium; Defect; Dendritic Cells; Development; Disease; Elements; Engineering; Enterobacteria phage P1 Cre recombinase; Enterocytes; Epithelial; Epithelial Cells; Etiology; Event; Experimental Models; Gene Expression Profiling; Gene Transfer Techniques; Growth; Human; IFNGR1 gene; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunoglobulin Class Switching; Infection; Infection Control; Inflammatory; Inflammatory Response; Interferon Type II; Intestinal Diseases; Lead; Licensing; Life; Ligation; Malignant - descriptor; Mediating; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Mutation; Outcome; Parasite Control; Parasites; Parasitic infection; Pathway interactions; Patients; Population; Production; Regulation; Resistance; Resistance to infection; Role; Signal Transduction; Site; Specificity; Sterility; Surveys; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Testing; Work; antimicrobial; diarrheal disease; enteric infection; enteric pathogen; experimental study; genetic approach; in vivo; insight; lymphoid structures; mouse model; novel; pathogen; programs; protective effect; resistance mechanism; response; single cell sequencing

Project Summary The ability of recently activated T cells to express the cell surface molecule CD40L allows them to communicate with other immune and non-immune populations. This molecule is of particular importance in the gut to help control the parasitic infection caused by Cryptosporidium. Here we leverage a novel, natural mouse model of Cryptosporidium to dissect the impact of the CD40-CD40L interaction in T cell-mediated resistance to infection in the gut. In this model, WT mice (like humans) develop sterile immunity mediated by T cell production of IFN-γ, but mice that lack CD40L mice (like humans) do not resolve infection. In addition, treatment of chronically infected CD40L-deficient mice with soluble (s)CD40L results in rapid parasite clearance. We will test if protective effect of CD40L may be explained by either I. its ability to promote T cell responses essential for resistance and/or II. because CD40L directly activates EC to limit parasite growth. We are uniquely equipped to utilize parasite transgenesis, combined with sophisticated genetic approaches to define the key cellular interactions that allows CD40L to determine the outcome of an enteric infection.

项目摘要 最近激活的T细胞表达细胞表面分子CD40L的能力使它们能够 与其他免疫和非免疫群体交流。这种分子在生物体中特别重要。 肠道有助于控制隐孢子虫引起的寄生虫感染。在这里，我们利用一种新颖的、自然的鼠标 用隐孢子虫模型研究CD40-CD40L相互作用对T细胞介导的T细胞免疫耐药的影响 肠道感染。在该模型中，WT小鼠(与人类一样)产生由T细胞介导的不育免疫 产生干扰素-γ，但缺乏CD40L的小鼠(如人类)不能解决感染。此外, S可溶性CD40L治疗慢性感染CD40L缺陷小鼠致快速寄生虫 通行证。我们将测试CD40L的保护作用是否可以通过任一I来解释。它促进T细胞的能力 对抗性和/或II.因为CD40L直接激活EC以限制寄生虫生长而必需的反应。我们 是利用寄生虫转基因的独特装备，与复杂的遗传方法相结合 明确关键的细胞相互作用，使CD40L能够确定肠道感染的结局。