Role of Intestinal Parasites on Regulating Immune Responses to Gut Antigens

肠道寄生虫在调节肠道抗原免疫反应中的作用

• 批准号: 10445670
• 负责人: Brian Todd Edelson
• 金额: $ 63.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445670
• 关键词: Address; Age; Allergens; Allergic Disease; Antigens; Antiparasitic Agents; Autoimmune Diseases; CD4 Positive T Lymphocytes; Cause of Death; Cells; Child; Cholera Toxin; Chronic; Cryptosporidium; Data; Development; Diarrhea; Disease; Effector Cell; Environment; Experimental Models; Food; Food Hypersensitivity; Generations; Helminths; Homeostasis; Human; Hybridomas; Hygiene; Immune Tolerance; Immune response; Incidence; Infection; Interleukin-10; Intestinal parasite; Intestines; Knowledge; Laboratories; Maintenance; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mus; Nematospiroides dubius; Oral; Organism; Parasite Control; Parasites; Parasitic infection; Pathogenicity; Pest Control; Phenotype; Prevention; Production; Regulatory T-Lymphocyte; Risk; Rodent; Role; Sanitation; Small Intestines; Specificity; T cell response; T-Cell Development; T-Lymphocyte; T-cell receptor repertoire; Testing; Time; Transgenic Mice; Transgenic Organisms; United States; Wild Type Mouse; cohort; diarrheal disease; dietary; effector T cell; food antigen; gastrointestinal; global health; gut colonization; helminth infection; immunopathology; in vivo; insight; intestinal homeostasis; novel; oral tolerance; pathogen; preservation; prevent; recurrent infection; response; tool; transcription factor

PROJECT SUMMARY/ABSTRACT Gastrointestinal parasitic infection is a widespread global health problem and can be a cause of significant morbidity. Nevertheless, there is limited information on how T cells respond to these parasites. In some cases, despite a robust T cell effector response to the parasite, tolerance to food antigens is maintained or enhanced. This has led to the notion that chronic parasitic infection could explain in part the hygiene hypothesis, which states that elimination of colonization or reduction of recurrent infections due to sanitation and pest control increases the risk of allergic and autoimmune diseases. We aim to understand how intestinal parasites induce effector T cell responses to parasitic antigens, and yet facilitate tolerance to food antigens present in the intestine. We will study two parasites that induce opposite T cell effector responses in mice. We will use a newly identified strain of Cryptosporidium tyzzeri, a commensal protozoan that induces a Th1 response, and H. polygyrus, a helminth that induces a Th2 response. The rationale for using parasites which elicit disparate T helper responses is to uncover potentially convergent mechanisms that may underly prevention of immunopathology during anti-parasitic responses and maintenance of tolerance to innocuous food antigens. In each infection, we will use TCR repertoire analysis to identify parasite-specific TCRs expressed by CD4+ T cells. This approach will allow us, for the first time, to precisely track the fate of such parasite-reactive T cells during these infections as they differentiate from naïve T cells to effectors or regulatory subsets. Given the central role of the transcription factor Bhlhe40 in regulating effector function and IL-10 production, we will also test its role in parasite-specific T cell fates and the development of a Tr1 phenotype which may provide immune tolerance to these parasites. In Aim 1 we will characterize the anti-parasite T cell response to H. polygyrus. In Aim 2, we will evaluate the mechanisms that regulate immune tolerance to Cryptosporidium. In Aim 3, we will determine how infection with these parasites impacts on the tolerogenic T cell response to food antigens and on the induction of food allergy. Overall, these studies will provide novel and important insights into how parasitic infections drive effector T cell responses to parasite antigens while simultaneously promoting tolerogenic or pathogenic responses to food antigens.

项目摘要/摘要 胃肠道寄生虫感染是一个普遍的全球健康问题，可能是导致 发病率。然而，关于T细胞如何对这些寄生虫做出反应的信息有限。在某些情况下， 尽管对寄生虫有强大的T细胞效应器反应，但对食物抗原的耐受性保持或提高了。 这导致了慢性寄生虫感染可以部分解释卫生假说的概念，该假说 指出，消除殖民或减少由于卫生和虫害防治而引起的反复感染 增加过敏和自身免疫性疾病的风险。我们的目标是了解肠道寄生虫是如何诱导 效应器T细胞对寄生虫抗原的反应，但仍促进对存在于 肠子。我们将研究两种寄生虫，它们在小鼠体内诱导相反的T细胞效应器反应。我们将使用 新发现的隐孢子虫Tyzzeri菌株，一种诱导Th1反应的共生原生动物，以及H. 多回，一种引起Th2反应的蠕虫。使用引起不同T细胞的寄生虫的理由 帮助者的反应是发现潜在的收敛机制，这些机制可能不足以预防 抗寄生虫反应和维持对无害食物抗原耐受性过程中的免疫病理学。在……里面 每一次感染，我们将使用TCR谱系分析来识别由CD4+T细胞表达的寄生虫特异性TCR 细胞。这种方法将使我们第一次能够精确跟踪这种寄生虫反应性T细胞的命运 在这些感染过程中，它们从幼稚的T细胞分化为效应者或调节亚群。给定 转录因子Bhlhe40在调节效应器功能和IL-10产生中的中心作用，我们还将 测试其在寄生虫特异性T细胞命运中的作用以及TR1表型的发展，这可能为 对这些寄生虫的免疫耐受性。在目标1中，我们将描述抗寄生虫T细胞对H. 多脑回。在目标2中，我们将评估调节对隐孢子虫免疫耐受的机制。在……里面 目的3，我们将确定感染这些寄生虫如何影响食物的耐受性T细胞反应 对抗原和对食物过敏的诱导。总体而言，这些研究将提供新的重要见解 研究寄生虫感染如何驱动效应器T细胞对寄生虫抗原的反应，同时促进 对食物抗原的耐受性或致病性反应。