The Role of Norovirus Interactions with the Epithelial Barrier in Acute Gastroenteritis

诺如病毒与上皮屏障相互作用在急性胃肠炎中的作用

• 批准号: 10679788
• 负责人: Amy Marie Peiper
• 金额: $ 4.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679788
• 关键词: ASBT protein; Acids; Acute; Adult; Animal Model; Antigen-Presenting Cells; Antiviral Agents; Antiviral Therapy; Bile Acids; Binding; Biological Models; Biology; Biopsy; Cells; Cessation of life; Childhood; Complex; Data; Dendrites; Detection; Development; Diarrhea; Disease; Enteral; Enterohepatic Circulation; Epithelial Cells; Epithelium; Fellowship; Gastroenteritis; Goals; Health; Human; Immune; Immune Targeting; Immunocompetent; Immunocompromised Host; Infection; Ingestion; Intestinal Diseases; Intestines; Kinetics; Lamina Propria; Liver; Mentors; Modeling; Movement; Mus; Norovirus; Pathogenesis; Pathogenicity; Pattern; Peyer' s Patches; Physicians; Population; Preventive treatment; Reporter; Research; Role; Route; Scientist; Severity of illness; Symptoms; Testing; Time; Training; Tropism; Vaccines; Villous; Viral; Virion; Virus; Virus Diseases; Virus Receptors; Virus Replication; Work; age group; burden of illness; career; cellular targeting; efficacy testing; ileum; improved; in vivo; intestinal epithelium; intestinal villi; mortality; mouse model; neonatal mice; novel; pathogen; pup; receptor; targeted treatment; therapeutic development; transcytosis; uptake; virology

Project Summary/Abstract Norovirus is the leading cause of severe childhood diarrhea around the world and a major cause of acute gastroenteritis in all age groups. There are no currently approved vaccines or targeted therapeutics for norovirus infection and very little is known about the pathogenic mechanisms underlying gastroenteritis symptoms. To gain further understanding of this important virus, murine norovirus has been used as a model system for many years and has led to significant advances in understanding norovirus biology. However, the absence of symptoms in immunocompetent adult mice infected with murine norovirus limits the applicability of this model to delineation of viral mechanisms of disease. We recently discovered that genetically wild-type neonatal mice develop acute, self-resolving diarrhea when infected with murine norovirus, a disease course that mirrors human norovirus infection. This novel small animal model of norovirus disease represents a major advance in the norovirus field since it will enable a complete characterization of viral disease mechanisms and ultimately serve as a platform to test the efficacy of antiviral compounds in vivo. Using this model, we have observed that murine norovirus infects subepithelial immune cells in the intestine but not intestinal epithelial cells. The mechanisms by which murine norovirus transcytoses the epithelial barrier to reach its immune cell targets during symptomatic infection is unknown and is the focus on Specific Aim 1 of my proposal. Specifically, I will test the hypothesis that murine norovirus uses two well-established routes for macromolecular transport across the intestinal epithelium, microfold cells and CX3CR1+ antigen presenting cells that express transepithelial dendrites. Although we did not observe viral replication in intestinal epithelial cells, there was abundant virus in these cells at the peak of diarrhea. This finding was surprising given that these cells do not express the virus receptor, nor do they support viral replication. In Specific Aim 2 of my proposal, I will test the hypothesis that progeny virus complexed with bile acids are endocytosed by intestinal epithelial cells via engagement of the apical sodium-dependent bile acid transporter. Overall, my research focuses on understanding norovirus interactions with the intestinal epithelium because these are undoubtedly key to the induction of diarrhea.

项目概要/摘要 诺如病毒是全世界严重儿童腹泻的主要原因，也是急性腹泻的主要原因。 各个年龄段的肠胃炎。目前尚无批准的诺如病毒疫苗或靶向治疗药物 感染，但对胃肠炎症状的致病机制知之甚少。为了获得 进一步了解这种重要的病毒，鼠诺如病毒多年来一直被用作模型系统 并在理解诺如病毒生物学方面取得了重大进展。然而，在没有症状的情况下 感染鼠诺如病毒的免疫活性成年小鼠限制了该模型描绘的适用性 疾病的病毒机制。我们最近发现，基因野生型新生小鼠会出现急性、 感染鼠诺如病毒时会出现自愈性腹泻，这种病程与人类诺如病毒相似 感染。这种新型诺如病毒疾病小动物模型代表了诺如病毒领域的重大进展 因为它将能够全面表征病毒疾病机制并最终作为一个平台 测试体内抗病毒化合物的功效。使用该模型，我们观察到鼠诺如病毒 感染肠道上皮下免疫细胞，但不感染肠上皮细胞。其机制 鼠诺如病毒在有症状感染期间转胞吞上皮屏障以到达其免疫细胞目标 未知，并且是我提案的具体目标 1 的重点。具体来说，我将检验小鼠的假设 诺如病毒使用两种成熟的途径进行大分子穿过肠上皮的运输， 表达跨上皮树突的微折叠细胞和CX3CR1+抗原呈递细胞。虽然我们做到了 没有观察到病毒在肠上皮细胞中的复制，在高峰期这些细胞中存在丰富的病毒 腹泻。这一发现令人惊讶，因为这些细胞不表达病毒受体，也不支持 病毒复制。在我提案的具体目标 2 中，我将检验子代病毒与 胆汁酸通过顶端钠依赖性胆汁酸被肠上皮细胞内吞 运输者。总的来说，我的研究重点是了解诺如病毒与肠上皮的相互作用 因为这些无疑是诱发腹泻的关键。