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: 10642945
• 负责人: Mary Kolb Estes
• 金额: $ 70.08万
• 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/10642945
• 关键词: Address; Animal Model; Antigens; Antiviral Agents; Apical; Attenuated; Bacteria; 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 Cells; Epithelium; 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; 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 Infections; Rotavirus Vaccines; Rotavirus disease; Route; Sampling; Serotonin; Severity of illness; Signal Pathway; Signal Transduction; Small Intestines; Surface; Testing; Translations; Vaccines; Vesicle; Viral; Viral Gastroenteritis; Virus; Virus Diseases; Virus Replication; Work; 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; improved; microbial community; microbiome; mortality; multidisciplinary; pathogen; pathogenic bacteria; pathogenic virus; pre-clinical; prevent; response; societal costs; stem cell derived tissues; success; technology development; 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.

项目总结