Human Gastrointestinal Biomimetics for Enteric Viral Infections

用于肠道病毒感染的人体胃肠道仿生学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胃肠炎 (GE) 是全球死亡的主要原因之一，我们的研究重点是人类轮状病毒。 (HRV) 和人类诺如病毒 (HuNoV)，这是全球病毒性 GE 的两个主要原因，导致超过 320,000 例每年都有人死亡，目前还没有针对这两种病毒的抗病毒药物，也没有针对 HuNoV 的疫苗。 HRV 的方法在高收入国家 (84-90%) 可用且有效，但疗效仍不理想 (45- 57%）在疾病负担最大的低收入环境中，HuNoV 感染会导致经济负担。这些数据强调了每年超过 40 亿美元的直接医疗成本和超过 600 亿美元的社会成本。需要继续投资研究以克服粘膜肠道疾病。这两种人类胃肠道病毒均不会感染小鼠；此外，HRV 在培养细胞中复制能力较差，而 HuNoV 则无法感染小鼠。使用组织干细胞衍生的人肠类器官 (HIO) 培养物近 50 年来一直无法培养。作为这些人类胃肠道病原体的复制模型，我们取得了一些显着的基本发现。研究结果包括：两种人类病毒在至少两种不同的肠道细胞类型（肠上皮细胞和肠内分泌细胞）在小肠中复制，HRV 也在结肠中复制。编码组织血液抗原 (HBGA)，但这些聚糖在 HBGA 表达中发挥不同的作用。不限制感染，但与严重的 HRV 疾病相关，而它是感染 HuNoV 所必需的。两种病毒与 HBGA 的相互作用均依赖于病毒株。 HRV 感染基底外侧和 HuNoV 感染顶部的不同途径产生感染的 HIO 培养物。囊泡中释放的新型 HRV，表现出与标准细胞培养衍生病毒不同的特性。令人惊讶的是，这两种病毒都能诱导上皮细胞对 III 型干扰素 (IFN) 的先天反应。不限制病毒复制，表明 III 型干扰素可能具有 HIO 以外的其他功能。多种HuNoV毒株的培养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感染的病理生理学和宿主反应的全面了解需要继续开发“人类迷你肠道”模型才能充分理解。人类-胃肠道病毒相互作用与发病机制有关，并改善对病毒感染的粘膜免疫反应。使用复杂的仿生培养物，我们建议回答两个生物学问题：基础和临床相关性：HRV 和 HuNoV 感染期间介导严重胃肠道疾病的机制是什么（目标 1），以及微生物与微生物之间的相互作用在病毒性 GE 的病理生理学中发挥什么作用（目标 2）？通过项目 2 和 3 以及我们的两个科学核心，我们预测我们的研究将取得进展并使人类能够器官仿生学作为理解人类粘膜感染的转化模型并充当桥梁临床前动物模型和首次人体临床试验之间。