Hepatitis C viral sensing by non-parenchymal liver cells (NPC)

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国最常见的血源性感染，总体患病率约为2%，全球估计有2亿慢性感染者。包括我们实验室的工作在内的大量证据支持这样一个概念，即多细胞免疫反应的协调和性质的早期事件对于决定病毒是否被清除或是否建立持久性至关重要。然而，关于非实质肝细胞（npc）在介导抗hcv反应中的作用知之甚少。我们建议研究浆细胞样树突状细胞、库普弗细胞和肝窦内皮细胞如何感知HCV感染。我们提供的证据表明，npc可以通过产生高水平的III型ifn（干扰素lambda 3）对丙型肝炎病毒产物（称为病原体相关分子模式或PAMP）产生反应。这些有趣的结果证实了最近的研究表明，编码干扰素lambda 3的单核苷酸多态性与丙型肝炎病毒的自发恢复有关。此外，我们已经证明NPCs在接种病毒或与受感染的肝细胞共培养后表达HCV核心。我们将确定npc衍生蛋白如何抑制病毒复制。此外，我们将探索HCV核心蛋白诱导调节性CD4+ T细胞的具体机制，从而将先天免疫反应和适应性免疫反应联系起来。本次申请涉及的人员包括研究生、博士后和教师。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an overall prevalence of ~2%, and an estimated 200 million chronically infected people worldwide. A substantial body of evidence, including work from our laboratory, supports the concept that early events in the coordination and nature of multi-cellular immune responses are critical in determining whether the virus is cleared or whether persistence is established. However, very little is known about the role of non-parenchymal liver cells (NPCs) in mediating anti-HCV responses. We propose to study how plasmacytoid dendritic cells, Kupffer cells and liver sinusoidal endothelial cells sense HCV infection. We present evidence that NPCs can respond to a viral product of hepatitis C (known as a pathogen-associated molecular pattern or PAMP) by producing high levels of Type III IFNs (interferon lambda 3). These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. Moreover, we have demonstrated that NPCs express HCV core after inoculation with virus or co-culture with infected hepatocytes. We will determine how NPC-derived proteins can inhibit viral replication. Furthermore, we will explore the specific mechanisms by which HCV core protein induces regulatory CD4+ T cells, thus linking innate and adaptive immune responses. The personnel involved in this application include graduate student, post-doctoral fellow and faculty.