Astrovirus modulation of gut immunity via goblet cells

星状病毒通过杯状细胞调节肠道免疫

• 批准号: 10456017
• 负责人: Valerie Cortez
• 金额: $ 10.74万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456017
• 关键词: Age; Antigens; Astrovirus; Bacteria; Binding; Cell Death; Cell physiology; Cells; Child; Childhood; Collaborations; Data; Dendritic Cells; Diagnostic tests; Diarrhea; Digestion; Enteral; Environment; Epithelial; Equilibrium; Exposure to; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Goblet Cells; Gut Mucosa; Homeostasis; Host Defense; Human; Immune; Immunity; Immunologics; Immunologist; Impairment; Infection; Infiltration; Inflammation; Intestines; Knowledge; Lamina Propria; Measures; Mediating; Mentors; Mentorship; Molecular; Mucins; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mucous body substance; Organ; Parasites; Pathogenesis; Pathology; Pathway interactions; Play; Positioning Attribute; Proteins; RNA; RNA Viruses; Research; Role; Small Intestinal Goblet Cell; Small Intestines; Specialized Epithelial Cell; Specificity; Surface; Testing; Training; Tropism; Viral; Virus; Virus Diseases; Virus Replication; antimicrobial; career; cell type; commensal bacteria; commensal microbes; enteric pathogen; exhaustion; food antigen; gastrointestinal epithelium; gut health; in vivo; insight; mouse model; novel; pathogen; prevent; receptor; response

PROJECT SUMMARY Astroviruses, positive-sense single-stranded RNA enteric viruses, are a leading cause of diarrhea worldwide. In comparison to other viruses that cause diarrhea astroviruses do not cause overt pathology, cell death, inflammation, or immune cell infiltration. We now believe this is related to their unique ability to infect small intestinal goblet cells, specialized epithelial cells that produce the mucus barrier and play a central role in the innate defenses of the gastrointestinal tract. Mucus not only protects against potential pathogens but also modulates interactions of the epithelial layer with commensal bacteria to promote a symbiotic environment that prevents self-digestion. Goblet cell dysfunction can trigger inflammation, and loss of the mucus barrier can impair host defenses against gastrointestinal diseases. Although the molecular interactions between goblet cells and bacteria have been characterized, few studies have focused on enteric virus interactions and their role in gut health. To fill this gap in knowledge, I propose using the murine model for astrovirus to study their unique tropism and the consequences of infection for gut health. My central hypothesis is that astrovirus hijacks the secretory pathway of goblet cells and this alters goblet cell immune and homeostatic functions. To test this hypothesis, in Aim 1 I will identify the molecular mechanisms by which astroviruses use secretory goblet cells for replication and in Aim 2 I will determine how infection alters the ability of goblet cells to form the mucus barrier and facilitate mucosal immune responses via the delivery of luminal antigens to the lamina propria. These data will reveal an entirely new facet of host-pathogen interactions that will be critical to our understanding of gut immunity and homeostasis in the context of viral infection.

项目概要 星状病毒是一种正义单链 RNA 肠道病毒，是全世界腹泻的主要原因。 与其他引起腹泻的病毒相比，星状病毒不会引起明显的病理、细胞死亡， 炎症或免疫细胞浸润。我们现在相信这与它们感染小型病毒的独特能力有关 肠杯状细胞是一种特殊的上皮细胞，可产生粘液屏障并在粘液屏障中发挥核心作用 胃肠道的先天防御。粘液不仅可以预防潜在的病原体，还可以 调节上皮层与共生细菌的相互作用，以促进共生环境 防止自我消化。杯状细胞功能障碍可引发炎症，而粘液屏障的丧失可 损害宿主对胃肠道疾病的防御能力。尽管高脚杯之间的分子相互作用 细胞和细菌已经被表征，很少有研究关注肠道病毒相互作用及其 对肠道健康的作用。为了填补这一知识空白，我建议使用星状病毒的小鼠模型来研究它们的 独特的趋向性以及感染对肠道健康的影响。我的中心假设是星状病毒 劫持杯状细胞的分泌途径，这会改变杯状细胞的免疫和稳态功能。到 为了检验这个假设，在目标 1 中，我将确定星状病毒利用分泌的分子机制 杯状细胞进行复制，在目标 2 中，我将确定感染如何改变杯状细胞形成 粘液屏障并通过将管腔抗原递送至层板促进粘膜免疫反应 固有的。这些数据将揭示宿主与病原体相互作用的全新方面，这对于我们的研究至关重要 了解病毒感染背景下的肠道免疫和体内平衡。