Immunity to Cryptosporidium

对隐孢子虫的免疫

• 批准号: 10529267
• 负责人: CHRISTOPHER A HUNTER
• 金额: $ 74.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529267
• 关键词: Adult; Affect; Age; Antigens; Area; Biological Models; Biology; Bioterrorism; C57BL/6 Mouse; Categories; Cause of Death; Cell Communication; Cell physiology; Cells; Child; Child Development; Child Mortality; Communities; Cryptosporidiosis; Cryptosporidium; Data; Defect; Dendritic Cells; Development; Disease; Disease Outbreaks; Drops; Engineering; Enterobacteria phage P1 Cre recombinase; Enterocytes; Epidemiology; Epithelial Cells; Etiology; Gene Expression Profile; Gene Expression Profiling; Genomics; Growth; Human; Hyperplasia; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologics; Immunologist; Incidence; Individual; Infection; Inflammatory; Interferon Type II; Intestinal Diseases; Knowledge; Life; Life Cycle Stages; Literature; LoxP-flanked allele; Malignant - descriptor; Malnutrition; Mediating; Methods; Modeling; Molecular; Mus; Organism; Organoids; Parasite Control; Parasites; Pathway interactions; Patients; Play; Population; Predisposition; Prevention; Process; Production; Reporter; Research; Resistance; Role; STAT1 gene; System; T cell response; T-Cell Development; T-Lymphocyte; Testing; Translations; Vaccines; Water; adaptive immunity; antimicrobial; asexual; chlorination; diarrheal disease; enteric pathogen; experience; genetic manipulation; immune clearance; in vivo; interest; mouse model; neglect; novel; pathogen; prevent; programs; resistance mechanism; response; single-cell RNA sequencing; tool; transmission process; vaccine development; villin; waterborne illness

The apicomplexan parasite Cryptosporidium is a leading cause of death due to diarrheal disease in young children, particularly in the context of malnutrition, milder infections often result in growth faltering. The incidence of cryptosporidiosis drops off sharply after the age of two in areas of high transmission, yet in regions with low transmission adults remain susceptible, as demonstrated by frequent outbreaks in the U.S. More than 50% of waterborne disease in the U.S. is caused by this parasite which is resistant to water chlorination and considered a category B potential bioterrorism agent. The epidemiology in children suggests that initial infection results in long lived protective immunity, a phenomenon also observed in the context of veterinary cryptosporidiosis. Harnessing this immunity into a vaccine could prevent the disease and dramatically impact child mortality and development. However, there are significant gaps in our knowledge of the mechanisms that underlie immunity to Cryptosporidium. We developed a new natural model of Cryptosporidium infection in immunocompetent C57BL/6 mice that mirrors important aspects of human cryptosporidiosis and in which host and parasite are genetically tractable. This proposal assembles an interdisciplinary team of experienced parasite molecular biologist and immunologist to define how the infected enterocyte senses infection, how it responds to and restricts infection, and how it interacts with dendritic cells and T cells to trigger and execute a protective immune response. This research will impact our fundamental understanding of immunity in the gut and drive translation towards prevention of an important contributor of child mortality. !

顶端复合体寄生虫隐孢子虫是导致年轻人腹泻病死亡的主要原因 儿童，特别是在营养不良的情况下，较轻微的感染往往会导致生长受阻。这个 在高传播地区，隐孢子虫病的发病率在两岁后急剧下降，但在 低传播成人的地区仍然容易感染，正如美国频繁爆发的疫情所表明的那样。 在美国，50%以上的水传播疾病是由这种对水有抵抗力的寄生虫引起的 氯化作用，并被认为是B类潜在的生物恐怖主义制剂。儿童的流行病学 表明初始感染会导致长期的保护性免疫，这一现象也在 兽医隐孢子虫病的背景。利用这种免疫力制成疫苗可以预防这种疾病。 并极大地影响儿童死亡率和发育。然而，我们在这方面存在着显著的差距 对隐孢子虫免疫机制的了解。我们开发了一种新的天然 免疫活性C57BL/6小鼠隐孢子虫感染模型的建立 人类隐孢子虫病，在这种疾病中，宿主和寄生虫在基因上是可处理的。这份建议书是由 一个由经验丰富的寄生虫分子生物学家和免疫学家组成的跨学科团队来定义 受感染的肠道细胞感知感染，它如何响应和限制感染，以及它如何与 树突状细胞和T细胞触发和执行保护性免疫反应。这项研究将对 我们对肠道免疫的基本了解，并推动翻译为预防 儿童死亡率的重要贡献者。 好了！