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.

摘要 隐孢子虫病是发展中国家幼儿腹泻的重要原因， 导致严重的死亡率和发病率。出现症状性疾病的儿童更有可能 患有营养不良和较低的身高和体重的年龄，这些缺陷持续多年后， 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， 在最初感染后的几年内无法茁壮成长。这些发现表明，肠道的改变， 在初始感染期间的功能建立了阻碍发展的持续性肠病。但 驱动这种临床结果的细胞和分子机制仍然没有解决。在早期发育过程中 在肠的某些组织中，杯状细胞在从肠腔取样抗原的过程中起着关键作用， 产生外周T调节细胞（pTreg），其抑制对饮食抗原的免疫应答， - 谢谢这一形成粘膜免疫系统的早期过程对维持口腔免疫至关重要。 生活中的宽容我们的研究验证了一个有趣的假设，即早期的隐孢子虫病会改变 通过破坏通常在这段时间内发展的口服耐受性来对内腔抗原产生应答。在 我们的初步研究表明，新生小鼠对C.细小病毒感染， 显示与抗原取样相关的杯状细胞功能缺陷。此外，我们还证明了C. parvum 感染的新生小鼠具有减少的pTreg细胞发育。我们将探讨一个假设， 隐孢子虫病通过两个主要目的破坏口服耐受性：1）确定 杯状细胞破坏抗原取样，2）探索破坏的pTreg发育对 口服耐受性这些研究将探索如何改变免疫反应，以饮食抗原或蛋白质。 微生物驱动炎症，损害肠道感染后的肠道功能。