Innate immunity to enteric virus infection by IFN-lambda stimulated-gene expression

摘要 由肠道病毒病原体如诺沃克病毒和轮状病毒引起的胃肠道疾病 严重的全球健康负担，对脆弱人群可能是致命的。对于这些和其他病毒 病原体、干扰素家族细胞因子是抗病毒免疫中最有效的成分之一。 回应。因此，干扰素通路是治疗疾病的临床相关靶点，也是一个重要的 继续进行基础研究的领域。我们和其他人已经证明，最新发现的类型 干扰素(III型干扰素，干扰素-λ)促进肠上皮细胞的天然抗病毒免疫，同时抑制 伴随I型干扰素反应的炎性损伤。我们最新的工作现在已经确定了一个 由细菌微生物区系刺激的动态平衡干扰素-λ反应，引发抗病毒基因 病毒暴露前的肠道上皮细胞。我们对小鼠轮状病毒感染的研究表明，体内平衡 干扰素-λ可先发制人地限制IEC的病毒感染。这项研究提案的目标是定义细胞 肠道内稳态干扰素-λ产生的来源(目标1)，其表达的机制基础(目标1) 2)及其对肠道病毒病的影响(目标3)。根据我们之前的工作和初步研究，我们的中央 假设肠道树突状细胞在短暂接触细菌时产生稳态干扰素-λ 产品，促进上皮细胞的先发制人的抗病毒反应。通过对本研究的研究 项目，我们将确定IECS中局部动态平衡干扰素-λ反应的基础，从而促进我们的 基本了解这种干扰素在肠道病毒病原体的抗病毒免疫中的作用。

ABSTRACT Gastrointestinal diseases caused by enteric viral pathogens such as norovirus and rotavirus impose a significant global health burden and can be lethal in vulnerable populations. For these and other viral pathogens, interferon (IFN) family cytokines are among the most potent elements of the antiviral immune response. Thus, IFN pathways are clinically relevant targets for treatment of disease, and are an important area for continued foundational research. We and others have shown that the most recently discovered type of IFN (type III IFN, IFN-λ) promotes innate antiviral immunity in intestinal epithelial cells (IECs) while minimizing inflammatory damage that can accompany a type I IFN response. Our most recent work has now identified a homeostatic IFN-λ response, stimulated by bacterial microbiota, that elicits antiviral genes within pockets of intestinal epithelium prior to viral exposure. Our studies of mouse rotavirus infection suggest that homeostatic IFN-λ preemptively limits viral infection of IECs. The objective of this research proposal is to define the cellular source of homeostatic IFN-λ production in the intestine (aim 1), the mechanistic basis for its expression (aim 2), and its impact on enteric viral disease (aim 3). Based on our prior work and preliminary studies, our central hypothesis is that intestinal dendritic cells produce homeostatic IFN-λ during transient exposure to bacterial products, promoting preemptive antiviral responses in epithelial cells. Through the studies of this research project, we will identify the basis of the localized homeostatic IFN-λ response in IECs, thereby advancing our fundamental understanding of this IFN type in the antiviral immunity to enteric viral pathogens.