Modeling Shigella Interaction with Innate Cells in Enteroid Co-Cultures to Inform Vaccine Development

模拟肠类共培养物中志贺氏菌与先天细胞的相互作用，为疫苗开发提供信息

• 批准号: 10190303
• 负责人: Eileen M. Barry
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190303
• 关键词: 5 year old; Animal Model; Attenuated; Attenuated Vaccines; Biopsy; Cells; Cessation of life; Characteristics; Child; Clinical; Coculture Techniques; Complex; Dendritic Cells; Dendritic cell activation; Developing Countries; Diarrhea; Disease; Disease Progression; Dysentery; Endemic Diseases; Engraftment; Epithelial; Escherichia coli; Evaluation; Event; Funding; Gastrointestinal Physiology; Health Priorities; Human; Immune; Immune response; Infection; Inflammatory Response; Innate Immune Response; Intervention; Kinetics; Lymphocyte; M cell; Modeling; Multi-Drug Resistance; Mutation; Pathogenesis; Pathogenicity; Patients; Physiological; Population; Process; Series; Shigella; Shigella Infections; Shigella Vaccines; Shigella flexneri; Shigella sonnei; Symptoms; System; Therapeutic Intervention; Virulence Factors; burden of illness; gastrointestinal; global health; immune activation; insight; intestinal epithelium; intraepithelial; macrophage; novel; pathogen; preventive intervention; response; synergism; therapy development; tool; transcytosis; uptake; vaccine acceptance; vaccine candidate; vaccine development; vaccine evaluation

Project 2: Modeling Shigella Interaction with Innate Cells in Enteroid Co-Cultures to Inform Vaccine Development Shigella is responsible for a significant burden of disease in multiple populations within the US and worldwide causing an estimated 163 million cases and >74,000 deaths per year. The greatest impact is in children under 5 years of age in developing countries where Shigella was identified as the most important pathogen causing diarrhea in 12-59 month old children. The widespread isolation of multiple drug resistant isolates limiting therapeutic interventions and the continued high levels of endemic disease underscore the significance of Shigella as a global health priority and reinforce the need for preventative interventions and vaccine development. Infection with Shigella results in diarrhea and dysentery following transcytosis of the epithelial barrier, invasion of gastrointestinal cells, intracellular replication and induction of a severe inflammatory response. Interaction with host innate immune cells including macrophages (MΦ), dendritic cells (DCs) and intraepithelial lymphocytes (IEL) are critical events in progression of disease symptoms as well as in initiation of a protective immune response. The human enteroid model provides a highly human relevant multicellular system that recapitulates important aspects of gastrointestinal physiology. Advances during the first P01 funding cycle included the addition of M cells and immune cell co-culture in enteroids. This complex model provides a system in which critical features of Shigella uptake, transcytosis, and engagement with immune cells can be identified which may serve as targets for interventional strategies. Using a series of isogenic Shigella strains with mutations in key virulence factors, we aim to define bacterial requirements for each stage of host engagement. Furthermore, the evaluation of a series of live attenuated vaccine strains that have been studied clinically will serve as tools to further understand bacterial requirements for the pathogenic process and allow determination of the utility of this model to distinguish promising vaccine candidates. Building on our current capability of M cell incorporation, we will use the M cell enteroid model to characterize sequential stages of Shigella-host interactions including the process of uptake and transcytosis, and subsequent interaction with critical innate immune cells. These studies will reveal novel aspects of host-pathogen interactions and ensuing innate immune responses to this pathogen that better reflect what occurs in humans; new insights will be provided that will guide intervention strategies.

项目2：建模志贺氏菌与肠道共培养中的先天细胞相互作用以告知疫苗 发展 Shigella负责全球世界内多个人口的疾病负担 估计造成1.63亿病例和> 74,000人死亡。 志贺氏菌被确定为最重要的病原体的发展中国家5岁以下 在12-59个月大的儿童中引起腹泻。 限制治疗干预措施和持续高水平的流行疾病强调了你 志贺氏菌作为全球健康的重要性，并强化了对投射干预措施的需求和 疫苗发育。 上皮屏障，胃肠道细胞的侵袭，严重的细胞内重复 炎症反应与包括巨噬细胞（Mφ）的宿主内部免疫细胞相互作用 细胞（DC）和上皮内淋巴细胞（IEL）是疾病症状进展的关键事件 随着保护性免疫反应的启动。 相关的多细胞系统，概括了胃肠道生理的重要方面 在第一个P01资金中，循环添加了M细胞和免疫细胞共培养。 这个复杂的模型提供了一个系统，其中志贺氏菌吸收，跨胞菌的关键特征和 可以识别与免疫细胞的互动，这可能是干预策略的目标。 我们使用一系列与关键病毒性因子突变的同源志贺氏菌菌株，我们旨在定义细菌 主机英语的每个阶段的要求。 临床上已经研究了疫苗STHAT，将使细菌了解细菌 病原过程过程的要求，并允许确定模型的效用 有望候选疫苗。 细胞肠模型以表征志贺氏菌宿主的顺序阶段，从而相互作用 摄取和跨性化，随后与关键的先天免疫细胞相互作用 揭示宿主 - 病原体相互作用的新颖方面以及随之而来的对这种病原体的先天免疫反应 更好地反映了人类的发生；