Cryptosporidiosis and Oral Tolerance

隐孢子虫病和口服耐受

• 批准号: 10741600
• 负责人: L. David Sibley
• 金额: $ 23.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741600
• 关键词: Adult; Age; Antigens; Architecture; Automobile Driving; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Clinical; Colon; Complex; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Defect; Developing Countries; Development; Dietary Factors; Disease; Environment; FOXP3 gene; Failure to Thrive; Food; Goblet Cells; Growth; Height; Human; IL18 gene; Immune response; Impairment; Individual; Infant; Infection; Inflammation; Intestines; Knowledge; Life; Livestock; Maintenance; Malnutrition; Molecular; Morbidity - disease rate; Mucosal Immune System; Mucosal Immunity; Mucous Membrane; Mus; Neonatal; Newborn Animals; Oocysts; Oral; Organism; Outcome; Peripheral; Play; Predisposition; Prevalence; Primary Infection; Process; Production; Regulatory T-Lymphocyte; Role; Sampling; Shapes; Signal Transduction; Testing; Time; Villus; Weight; Zoonoses; age related; community-level factor; diarrheal disease; dietary; dysbiosis; enteric infection; food antigen; mesenteric lymph node; microbial community; microbiome; microbiota; mortality; mouse model; neonatal infection; neonatal mice; oral tolerance; prevent; response

ABSTRACT Cryptosporidiosis is an important cause of diarrheal disease in young children in the developing world where it causes significant mortality and morbidity. Children that present with symptomatic disease are more likely to suffer from malnutrition and lower height and weight per age, and these deficiencies persist for years after the primary infection resolves. Surprisingly even asymptomatic cases can be associated with malnutrition and failure to thrive for several years beyond the initial infection. These findings suggest that alterations in intestinal function during the initial infection establish persistent enteropathy that stunts development. However, the cellular and molecular mechanisms driving this clinical outcome remain unresolved. During early development of the intestine, Goblet cells play a critical role in sampling of antigens from the gut lumen in a process that generates peripheral T regulatory cells (pTreg), which suppress immune responses to dietary antigens and commensals. This early process in shaping the mucosal immune system is critical to maintenance of oral tolerance later in life. Our study examines the intriguing hypothesis that cryptosporidiosis in early life alters responses to lumenal antigens by disrupting oral tolerance that normally develops during this time period. In preliminary studies we have shown that neonatal mice, which are highly susceptible to C. parvum infection, show defects in Goblet cell functions related to antigenic sampling. Furthermore we show that C. parvum infected neonatal mice have reduced development of pTreg cells. We will explore the hypothesis that cryptosporidiosis disrupts oral tolerance through two main aims: 1) determine the molecular mechanism for disruption of antigen sampling by Goblet cells, 2) explore the consequence of disrupted pTreg development on oral tolerance. These studies will explore how altered immune responses to dietary antigens or commensal organisms drive inflammation that impairs gut function following enteric infection.

抽象的 隐孢子虫病是在其发展中国家的幼儿腹泻病的重要原因 引起重大死亡率和发病率。出现有症状疾病的孩子更有可能 患有营养不良，每个年龄段的高度和体重较低，这些缺陷持续了多年 原发性感染消退。令人惊讶的是，即使是无症状的病例也可能与营养不良有关 未能在初期感染之外蓬勃发展几年。这些发现表明肠道的改变 最初感染期间的功能确立了特技发育的持续性肠病。但是， 驱动该临床结果的细胞和分子机制仍未解决。在早期发展期间 在肠道中，杯状细胞在一个过程中在肠腔中取样的抗原中起着至关重要的作用 产生周围T调节细胞（PTREG），该细胞抑制了对饮食抗原的免疫反应和 共生。塑造粘膜免疫系统的早期过程对于维持口服至关重要 耐受性的耐受性。我们的研究研究了早期的隐孢子虫病的有趣假设改变了 通过破坏通常在此期间发展的口服耐受性来反应对腔抗原。在 初步研究，我们已经表明，新生儿小鼠非常容易受到孢子虫感染的影响 显示与抗原采样有关的杯状细胞功能中的缺陷。此外，我们表明C. parvum 被感染的新生小鼠的PTREG细胞发育降低。我们将探讨以下假设 隐孢子虫病通过两个主要目的破坏口服耐受性：1）确定分子机制 杯状细胞破坏抗原采样，2）探讨ptreg发育局面的后果 口服耐受性。这些研究将探讨如何改变对饮食抗原或共生的免疫反应改变 生物体驱动炎症，会损害肠道感染后肠道功能。