Cryptosporidiosis and Oral Tolerance

摘要 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 患有营养不良和身高和体重较低的年龄，这些缺陷在 原发感染痊愈。令人惊讶的是，即使是没有症状的病例也可能与营养不良和 在最初感染后的几年里未能茁壮成长。这些发现表明，肠道的变化 在最初感染期间的功能建立了阻碍发育的持续性肠病。然而， 推动这一临床结果的细胞和分子机制仍未解决。在早期开发期间 产生外周T调节细胞(PTreg)，抑制对饮食抗原的免疫反应，并 共生关系。这一早期形成粘膜免疫系统的过程对口腔的维持至关重要 在以后的生活中宽容。我们的研究检验了一个有趣的假设，即早期生活中的隐孢子虫病会改变 通过破坏口服耐受性对管腔抗原的反应，这种耐受性通常发生在这一时期。在……里面 我们的初步研究表明，新生小鼠对微小弧菌感染高度敏感， 显示与抗原采样相关的杯状细胞功能缺陷。此外，我们还证明了微小隐孢子虫 感染的新生小鼠减少了pTreg细胞的发育。我们将探讨这样的假设 隐孢子虫病通过两个主要目的破坏口服耐受性：1)确定 杯状细胞对抗原采样的干扰，2)探讨pTreg发育中断对 口服耐受性。这些研究将探索如何改变对饮食抗原或共生的免疫反应 肠道感染后，微生物会引发炎症，损害肠道功能。

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.