Astrovirus modulation of gut immunity via goblet cells

项目摘要 星状病毒，正义单链RNA肠道病毒，是全球腹泻的主要原因。 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学，细胞死亡， 炎症或免疫细胞浸润。我们现在认为这与它们独特的感染小病毒的能力有关。 肠杯状细胞，专门的上皮细胞，产生粘液屏障，并发挥核心作用， 胃肠道的先天防御。粘液不仅可以防止潜在的病原体， 调节上皮层与肠道细菌的相互作用，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，粘液屏障的丧失可 损害宿主对胃肠道疾病防御。尽管酒杯之间的分子相互作用 细胞和细菌的特征，很少有研究集中在肠道病毒的相互作用和它们的 在肠道健康中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 独特的向性和感染对肠道健康的后果。我的主要假设是星状病毒 劫持杯状细胞的分泌途径，从而改变杯状细胞的免疫和稳态功能。到 为了验证这一假设，在目标1中，我将确定星状病毒利用分泌功能的分子机制。 在目标2中，我将确定感染如何改变杯状细胞形成细胞的能力。 粘液屏障，并通过将管腔抗原递送至粘膜层而促进粘膜免疫应答 propria。这些数据将揭示宿主-病原体相互作用的一个全新方面，这对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。

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.