Human Gastrointestinal Biomimetics for Enteric Viral Infections

用于肠道病毒感染的人体胃肠道仿生学

• 批准号: 10462791
• 负责人: Mary Kolb Estes
• 金额: $ 35.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462791
• 关键词: Address; Animal Model; Antigens; Antiviral Agents; Apical; Attenuated; Bile Acids; Bile fluid; Binding; Biochemical; Biological; Biology; Biomimetics; Blood; Blood Group Antigens; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Ceramides; Cessation of life; Clinical; Clinical Trials; Colon; Communicable Diseases; Complex; Country; Cultured Cells; Data; Development; Disease; Engineering; Enteral; Enteric Nervous System; Enterobacter; Enterocytes; Environment; Epithelial; Epithelial Cells; Exhibits; Functional disorder; Gastroenteritis; Gastrointestinal Diseases; Genetic; Genetic Transcription; Health Care Costs; Human; Immune; Immune Evasion; Immune response; Immune system; Income; Infection; Interferons; Intervention; Intestines; Investments; Klebsiella; Knowledge; Laboratories; Lead; Life; Link; Low income; Mediating; Microbe; Modeling; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Nerve; Neurons; Norovirus; Organ; Organoids; Outcome; Pathogenesis; Physiological; Physiology; Play; Polysaccharides; Predisposition; Production; Property; Research; Role; Rotavirus; Rotavirus Vaccines; Rotavirus disease; Route; Sampling; Serotonin; Severity of illness; Signal Pathway; Signal Transduction; Small Intestines; Surface; Testing; Translations; Vaccines; Vesicle; Viral Gastroenteritis; Virus; Virus Diseases; Virus Replication; Work; base; burden of illness; cell immortalization; cell type; clinically relevant; co-infection; enteric virus infection; enteroaggregative Escherichia coli; epidemiology study; first-in-human; flexibility; gastrointestinal; gastrointestinal infection; human pathogen; improved; microbial community; microbiome; mortality; multidisciplinary; pathogen; pathogenic bacteria; pathogenic virus; pre-clinical; prevent; response; societal costs; stem cell derived tissues; success; translational model; translational potential; vaccine failure; vaccine response; virology; virus host interaction

PROJECT SUMMARY Gastroenteritis (GE) is among the leading causes of mortality globally. Our research focuses on human rotavirus (HRV) and human norovirus (HuNoV), the two leading causes of viral GE worldwide causing over 320,000 deaths annually. No antivirals are available for either virus and there is no vaccine for HuNoVs. While vaccines to HRV are available and are effective in high-income countries (84-90%), the efficacy remains suboptimal (45- 57%) in low-income settings where the burden of disease is greatest. Economically, HuNoV infections result in over $4 billion in direct healthcare costs and over $60 billion in societal costs each year. These data underscore the need for continued investment in studies to overcome mucosal enteric disease. Both these human GI viruses do not infect mice; further, HRV replicates poorly in cultured cells, and HuNoV was noncultivatable for over almost 50 years. Using tissue stem cell-derived human intestinal organoid (HIO) cultures as a replication model for these human GI pathogens, we made some remarkable fundamental discoveries. Key findings include: both human viruses replicate in at least two distinct intestinal cell types (enterocytes and enterendocrine cells) in the small intestine, and HRVs also replicate in the colon. Each virus binds to genetically encoded histo-blood antigens (HBGAs) but these glycans play different roles in infection. HBGA expression does not restrict infection but correlates with severe HRV disease while it is required for infection with HuNoV. Interactions with HBGA are strain-dependent for both viruses. Each virus infects the polarized epithelium by a different route with HRVs infecting basolaterally and HuNoVs infecting apically. Infected HIO cultures produce a new form of HRV released in vesicles that exhibit different properties from standard cell-culture derived virus. Both viruses induce a predominant epithelial innate response of type III interferon (IFN); surprisingly this does not restrict virus replication suggesting type III IFN may have other functions than being antiviral. HIOs allow cultivation of multiple HuNoV strains and bile is a critical factor for replication. Although these previous studies using epithelial-only HIOs provide new knowledge on HRV and HuNoV infections, we still lack a comprehensive understanding of the pathophysiology and host responses that lead to life-threatening disease. Continued development of “human mini-gut” models is required to fully understand human-GI virus interactions linked to pathogenesis and improve mucosal immune responses to viral infections. Using complex biomimetic cultures, we propose to answer two biological questions of fundamental and clinical relevance: What mechanisms mediate severe GI disease during infection with HRV and HuNoV (Aim 1), and what is the role of microbe-microbe interactions in the pathophysiology of viral GE (Aim 2)? Through interactions with Projects 2 and 3 and our two Scientific Cores, we predict our studies will advance and enable human organ biomimetics as translational models to understand human mucosal infections and to serve as a bridge between preclinical animal models and first-in-human clinical trials.

项目摘要 胃肠炎（GE）是全球死亡率的主要原因之一。我们的研究侧重于人轮状病毒 （HRV）和人类诺如病毒（Hunov），这是全球病毒GE的两个主要原因，造成32万以上 每年死亡。任何一种病毒都没有抗病毒药物，也没有用于Hunovs的疫苗。而疫苗 HRV可用，在高收入国家有效（84-90％），有效性仍然优化（45-- 57％）在疾病燃烧最大的低收入环境中。从经济上讲，霍诺夫感染导致 每年的直接医疗保健费用超过40亿美元，社会成本超过600亿美元。这些数据强调 需要继续投资的研究以克服粘膜肠道疾病。 这两种人GI病毒均未感染小鼠。此外，HRV在培养的细胞中复制不佳，Hunov是 近50年来不可培养。使用组织干细胞衍生的人肠癌（HIO）培养物 作为这些人类胃肠道病原体的复制模型，我们做出了一些显着的基本发现。钥匙 发现包括：两种人类病毒在至少两种不同的肠细胞类型（肠细胞和 小肠中的肠分泌细胞），HRV也在结肠中复制。每种病毒在遗传上结合 编码的组织血液抗原（HBGAS），但这些聚糖在感染中起着不同的作用。 HBGA表达方式 不限制感染，而是与严重的HRV疾病有关，同时需要使用Hunov感染。 与HBGA的相互作用在这两种病毒中均依赖于应变。每种病毒通过A感染了极化上皮 与HRV的不同途径受感染的基础，并在顶端感染了霍诺夫。感染的Hio培养物产生了 HRV在蔬菜中释放的新形式，这些蔬菜与标准细胞培养病毒暴露了不同的特性。 这两种病毒诱导了III型干扰素（IFN）的主要上皮天生反应；令人惊讶的是，这确实如此 没有限制病毒复制表明III型IFN可能具有抗病毒功能。 hios允许 培养多个霍诺夫菌株和胆汁是复制的关键因素。 尽管这些先前使用仅上皮HIO的研究提供了有关HRV和HUNOV的新知识 感染，我们仍然缺乏对导致病理生理学和宿主反应的全面理解 威胁生命的疾病。需要持续开发“人类迷你态”模型才能充分理解 与发病机理并改善粘膜免疫反应有关病毒感染的人类GI病毒相互作用。 使用复杂的仿生培养物，我们建议回答两个基本和临床的生物学问题 相关性：哪些机制在HRV和HUNOV感染期间介导了严重的GI疾病（AIM 1），以及 微生物相互作用在病毒GE的病理生理学中的作用是什么（AIM 2）？通过互动 随着项目2和3和我们的两个科学核心，我们预测我们的研究将进步并使人类能够 器官仿生学作为翻译模型，以了解人类粘膜感染并充当桥梁 在临床前动物模型和人类临床试验之间。