Hepatitus C virus-induced inflammasome and lipid metabolism

 描述（由申请人提供）：丙型肝炎病毒（HCV）感染约3%的世界人口，是与肝硬化和肝细胞癌相关的最常见病原体。每年有300 - 400万人感染，60-80%的受感染成年人成为慢性感染并患有慢性肝炎，随后进展为终末期肝病，如肝纤维化、肝硬化和肝癌。HCV引起慢性进行性肝损伤的机制尚未完全确定。HCV在其生命周期的所有方面对宿主脂质的依赖以及病毒对宿主脂质代谢的伴随调节是HCV生物学的独特特征。HCV改变脂质体内平衡，导致细胞内脂滴积聚，表现为“脂肪肝/脂肪肝”，这是与慢性HCV感染相关的常见表型。有趣的是，脂肪肝与终末期肝病的进展有关，通常被认为是肝纤维化和肝硬化的前奏。慢性HCV感染期间的肝脏炎症被认为是肝脏疾病和进展为肝癌的主要催化剂。有趣的是，最近的研究表明炎症信号和宿主脂质代谢之间存在复杂的联系。慢性炎症在HCV感染相关的肝脏脂质代谢改变中的作用至今尚未研究。我们最近发现，HCV促进了受感染肝细胞中NLRP 3-炎性体的活化，这可能有助于与感染相关的慢性炎症。炎性小体激活通常被认为是解决感染。相反，我们的初步研究表明，HCV利用NLRP 3-炎性体来调节脂质代谢和促进病毒增殖。在本研究中，我们将尝试进一步探索和理解NLRP 3-炎性体与HCV感染过程中脂质代谢之间的有趣关系。基于我们的初步研究结果，我们假设HCV诱导的NLRP 3-炎性体介导LD的生物合成并促进HCV的组装和释放。本研究的目的是阐明与这些过程相关的潜在机制。为了实现我们的目标，我们提出了三个具体的目标;在目标1中，我们将确定NRRP 3-炎性体如何促进HCV感染细胞中的SREBP成熟和活性，在目标2中，我们将确定NLRP 3-炎性体在脂滴生物发生中的作用，在目标3中，我们将定义NLRP 3-炎性体在HCV增殖中的作用。这项研究具有重要意义，涉及HCV感染中炎症和肝脏脂质代谢之间的新的和未表征的联系，并将揭示重要线索，增强我们对HCV生物学/生命周期和肝脏疾病病理生理学的理解。从拟议的研究中获得的结果将为开发HCV感染和相关肝脏疾病的有效治疗开辟潜在的新途径。

 DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) infects about 3% of the world's population and is the most common etiological agent associated with liver cirrhosis and hepatocellular carcinoma. Annually 3-4 million people acquire infection and 60-80% of the infected adults become chronically infected and suffers from chronic hepatitis, which then subsequently progresses into end-stage liver diseases such as liver fibrosis, cirrhosis and liver cancer. The mechanisms by which HCV causes chronic progressive liver damage are not completely characterized. The reliance of HCV on host lipids for all facets of its lifecycle and th concomitant modulation of the host lipid metabolism by the virus is a unique feature of HCV biology. HCV alters the lipid homeostasis leading to the accumulation of intracellular lipid droplets that manifests into `hepatosteatosis/fatty liver' a common phenotype associated with chronic HCV infection. Intriguingly, hepatosteatosis is associated with progression to end stage liver diseases and is often considered a prelude to liver fibrosis and cirrhosis. Hepatic inflammation during chronic HCV infection is considered to be the primary catalyst for liver disease and progression to liver cancer. Interestingly, recent studies imply an intricate connection between inflammatory signaling and host lipid metabolism. The role of chronic inflammation in HCV-infection associated alteration of hepatic lipid metabolism has not been studied so far. We recently showed that HCV promotes the activation of the NLRP3-inflammasome in infected hepatocytes, which likely contributes to chronic inflammation associated with infection. Inflammasome activation is conventionally considered to resolve the infection. In contrast, our preliminary studies reveal that HCV exploits the NLRP3-inflammasome to modulate lipid metabolism and to facilitate viral proliferation. In this proposal we will attempt to further explore and understand this intriguing relation between NLRP3-inflammasome and lipid metabolism during HCV infection. Based on our preliminary findings we hypothesize that HCV-induced NLRP3-inflammasome-mediates LDs biogenesis and facilitate HCV assembly and release. The objective of this study is to elucidate the underlying mechanisms associated with these processes. In pursuit of our objective we propose three specific aims; in Aim 1, we will determine how NRLP3-inflammasome promotes SREBPs maturation and activity in HCV infected cells, in Aim 2, we will determine the role of the NLRP3-inflammasome in lipid droplets biogenesis, and in Aim 3, we will define the role of the NLRP3-inflammasome in HCV proliferation. The proposed research is highly significant and deals with the novel and uncharacterized link between inflammation and hepatic lipid metabolism in HCV infection and will unveil important clues enhance our understanding of HCV biology/life cycle and pathophysiology of liver diseases. The results obtained from the proposed studies will open potential new avenues for developing efficient therapy to HCV infection and associated liver diseases.