Intestinal Stem Cell Responses to Cryptosporidium Infection

肠道干细胞对隐孢子虫感染的反应

• 批准号: 10330758
• 负责人: Xian-Ming Chen
• 金额: $ 19.63万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-29 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330758
• 关键词: 2 year old; AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Affect; Age; Attenuated; Biochemical; Cell Count; Cell Proliferation; Cells; Child; Code; Country; Cryptosporidiosis; Cryptosporidium; Data; Developing Countries; Development; Diarrhea; Disease; Enterocytes; Event; Exclusion; Exhibits; Foundations; Functional disorder; Genes; Growth and Development function; HIV diagnosis; Health; Health Services Accessibility; Highly Active Antiretroviral Therapy; Human; Hyperplasia; Immune; In Vitro; Incidence; Infection; Intestines; Life; Metabolism; Modeling; Molecular; Morbidity - disease rate; Morphology; Mucous Membrane; Mus; Natural regeneration; Outcome; Parasites; Pathogenesis; Pathologic; Patients; Physiological Processes; Population; Primary Infection; Proliferating; Property; Research; Rotavirus; Signal Pathway; Site; Small Intestines; Societies; Surface; Tissues; Villus; cell type; cognitive development; cost; effective therapy; enteric infection; experience; gastrointestinal epithelium; gut microbiota; in vivo; in vivo Model; intestinal crypt; intestinal epithelium; intestinal homeostasis; intestinal villi; microbiome alteration; mortality; novel therapeutic intervention; nutrition; opportunistic pathogen; pathogen; response; self-renewal; stem cell biomarkers; stem cell function; stem cell population; stem cells

Summary Cryptosporidium remains an important opportunistic pathogen in AIDS patients who do not have access to HAART treatment. This parasite infects the gastrointestinal epithelium in humans; infection in AIDS patients often leads to life-threatening illness. Cryptosporidium is also a common cause of diarrhea in young children in developing countries. Indeed, infection with Cryptosporidium shows significant association with mortality in young children and appears to predispose children to enteric infection with lasting deficits in age-appropriate body growth and cognitive development. The underlying molecular mechanisms are unclear. The primary infection site of Cryptosporidium in human is the small intestine, one of tissues in the body that regenerates the most quickly. In our preliminary study, we observed that Cryptosporidium infection is limited to the villi (mainly enterocytes) of intestinal epithelium. Nevertheless, infection causes a significant decrease in intestinal stem cell (ISC) numbers (as well as the expression levels of several ISC markers). We also identified a panel of genes whose expression levels are significantly altered in enterocytes following infection. Some of these genes code important components of the signaling pathways in the enterocyte-ISC network and thus, may be involved in Cryptosporidium-induced ISC dysfunction. Therefore, we hypothesize that Cryptosporidium infection in the villi of intestinal epithelium impedes ISC function in the crypts through changes of signaling pathways in the enterocyte-to-ISC network. We will use in vitro, ex vivo, and in vivo infection models and complementary biochemical, molecular, and morphologic approaches to characterize the dysfunction of ISC populations (ISC plasticity) during Cryptosporidium infection (Aim 1) and identify the signaling pathways pertinent to ISC dysfunction induced by infection (Aim 2). With the completion of these aims, we will have determined the ISC plasticity during Cryprosporidium infection and identified which signaling pathways are specifically affected by infection leading to ISC dysfunction. These outcomes will establish a foundation on which to build long-term, mechnistic studies to define the pathogenesis (particularly the long-lasting effects) of Cryptosporidium infection in the intestine.

总结 隐孢子虫仍然是一个重要的机会致病菌在艾滋病患者谁没有获得 HAART治疗。这种寄生虫感染人类的胃肠道上皮;艾滋病患者的感染 往往会导致危及生命的疾病。隐孢子虫也是一种常见的原因，腹泻的幼儿， 发展中国家事实上，隐孢子虫感染显示出与死亡率显著相关， 幼儿，似乎容易使儿童肠道感染与持久的赤字，在年龄适当的 身体生长和认知发展。潜在的分子机制尚不清楚。主 隐孢子虫在人体内的感染部位是小肠，小肠是体内再生 最快。在我们的初步研究中，我们观察到隐孢子虫感染仅限于绒毛（主要是 肠上皮细胞）。然而，感染导致肠干细胞显著减少， 细胞（ISC）数量（以及几种ISC标志物的表达水平）。我们还发现了一组 感染后肠上皮细胞中表达水平显著改变的基因。其中一些基因 编码肠细胞-ISC网络中信号通路的重要组分，因此， 参与隐孢子虫诱导的ISC功能障碍。因此，我们假设隐孢子虫 肠上皮绒毛中的感染通过信号传导的改变阻碍了隐窝中ISC的功能 肠细胞-ISC网络中的通路。我们将使用体外、离体和体内感染模型， 互补的生物化学、分子和形态学方法来表征ISC功能障碍 群体（ISC可塑性）在隐孢子虫感染（目的1），并确定信号通路 与感染诱导的ISC功能障碍有关（目的2）。随着这些目标的实现，我们将 确定了在Cryprosporidium感染过程中ISC的可塑性，并确定了哪些信号通路是 特别是受感染的影响，导致ISC功能障碍。这些成果将奠定基础， 建立长期的，机制研究，以确定发病机制（特别是长期影响）， 肠内隐孢子虫感染。