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

基本信息

批准号：
10651714
负责人：
Brian Todd Edelson
金额：
$ 63.17万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10651714
关键词：
Address Africa Age Allergens Allergic Disease Antigen Presentation Antigens Antiparasitic Agents Autoimmune Diseases CD4 Positive T Lymphocytes Cause of Death Cells Child Cholera Toxin Chronic Cryptosporidium Data Development Diarrhea Disease Disparate Effector Cell Environment Eragrostis 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

项目摘要

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.

项目概要/摘要胃肠道寄生虫感染是一个普遍存在的全球健康问题，可能是导致重大疾病的原因之一。然而，在某些情况下，关于 T 细胞如何应对这些寄生虫的信息有限。尽管 T 细胞效应器对寄生虫有强烈的反应，但对食物抗原的耐受性得以维持或增强。这导致了这样一种观念，即慢性寄生虫感染可以部分解释卫生假说，该假说指出通过卫生和害虫防治消除定植或减少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如何诱发。效应T细胞对寄生抗原的反应，并且促进对存在于食物中的抗原的耐受性我们将研究两种在小鼠体内诱导相反 T 细胞效应反应的寄生虫。新鉴定的泰泽隐孢子虫菌株（一种诱导 Th1 反应的共生原生动物）和 H. Polygyrus，一种诱导 Th2 反应的蠕虫，使用引起不同 T 的寄生虫的基本原理。辅助反应的目的是发现潜在的趋同机制，这些机制可能是预防的基础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。每次感染，我们将使用 TCR 库分析来识别 CD4+ T 表达的寄生虫特异性 TCR 这种方法将使我们第一次能够精确追踪这种寄生虫反应性 T 细胞的命运。在这些感染过程中，它们从初始 T 细胞分化为效应子或调节子集。转录因子 Bhlhe40 在调节效应子功能和 IL-10 产生中的核心作用，我们还将测试其在寄生虫特异性 T 细胞命运和 Tr1 表型发展中的作用，这可能提供在目标 1 中，我们将描述针对幽门螺旋杆菌的抗寄生虫 T 细胞反应。在目标 2 中，我们将评估调节隐孢子虫免疫耐受的机制。目标 3，我们将确定这些寄生虫的感染如何影响 T 细胞对食物的耐受反应总的来说，这些研究将提供新颖且重要的见解。研究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耐受性或致病性反应。