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. !

隐孢子虫是一种顶复形寄生虫，是导致年轻人因疟疾而死亡的主要原因 儿童，特别是在营养不良的情况下，较轻的感染往往导致生长迟缓。的 在高传播地区，隐孢子虫病的发病率在两岁后急剧下降， 成人传播率低的地区仍然易感，美国的频繁暴发就证明了这一点。 美国超过50%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，被认为是B类潜在的生物恐怖主义制剂。儿童流行病学 表明初始感染导致长期保护性免疫，这一现象也在 兽医隐孢子虫病利用这种免疫力制成疫苗可以预防这种疾病 严重影响儿童死亡率和发展。然而，我们在这方面存在着巨大的差距。 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C57 BL/6小鼠隐孢子虫感染模型，反映了 人类隐孢子虫病，其中宿主和寄生虫在遗传上是易处理。该提案汇集了 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， 感染的肠上皮细胞感觉感染，它如何响应和限制感染，以及它如何与 树突状细胞和T细胞来触发和执行保护性免疫反应。这项研究将影响 我们对肠道免疫力的基本理解，并推动翻译向预防肠道疾病， 是儿童死亡率重要因素。 !