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.

项目总结/摘要 胃肠道寄生虫感染是一个普遍的全球性健康问题， 发病率然而，关于T细胞如何对这些寄生虫作出反应的信息有限。在某些情况下， 尽管对寄生虫有强有力的T细胞效应应答，但对食物抗原的耐受性得以维持或增强。 这导致了慢性寄生虫感染可以部分解释卫生假说的概念， 指出，由于卫生和虫害防治， 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如何诱导 效应T细胞对寄生虫抗原的应答，但促进对存在于宿主细胞中的食物抗原的耐受性。 肠子我们将研究两种寄生虫在小鼠中诱导相反的T细胞效应反应。我们将使用一个 新鉴定的隐孢子虫Tyzzeri菌株，一种诱导Th 1应答的寄生性原生动物，和H. polygyrus，一种诱导Th 2反应的蠕虫。使用引起不同T细胞的寄生虫的原理 辅助反应是揭示潜在的趋同机制，可能是预防 抗寄生虫反应期间的免疫病理学和对无害食物抗原的耐受性的维持。在 每次感染，我们将使用TCR库分析来鉴定由CD 4 + T细胞表达的寄生虫特异性TCR。 细胞这种方法将使我们能够第一次精确地追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T细胞分化为效应细胞或调节亚群。鉴于 转录因子Bhlhe 40在调节效应子功能和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细胞命运和Tr 1表型发展中的作用， 免疫耐受这些寄生虫。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，我们将评估调节隐孢子虫免疫耐受的机制。在 目的3，我们将确定这些寄生虫感染如何影响致耐受性T细胞对食物的反应 抗原和诱导食物过敏。总的来说，这些研究将提供新的和重要的见解， 寄生虫感染如何驱动效应T细胞对寄生虫抗原的反应，同时促进 对食物抗原的致耐受性或致病性反应。