A chicken model to study hepatitis E virus pathogenesis

研究戊型肝炎病毒发病机制的鸡模型

基本信息

  • 批准号:
    9788856
  • 负责人:
  • 金额:
    $ 39.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-06-15 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary: Hepatitis E virus (HEV) infects >20 million people worldwide annually leading to >44,000 deaths due to HEV-related hepatobiliary diseases. A unique feature of HEV infection is fulminant hepatitis with high mortality of >25% in pregnant women. Due to the lack of an animal model, the underlying mechanism in the pathogenesis of HEV-associated fulminant hepatitis during pregnancy is unknown. The elevated levels of sex hormones such as progesterone and estrogen during pregnancy are known to promote certain virus replications including HEV. Accumulating evidence indicate that HEV replication is sex hormone-dependent, as HEV replication was significantly enhanced in the presence of sex hormones or pregnancy sera in infected cells. The recent discovery of HEV from rabbits led to the development of a pregnancy model for HEV, as fulminant hepatitis with high mortality was convincingly and independently reproduced in HEV-infected pregnant rabbits. The long-term goal is to identify the host (hormonal and immunological) and viral factors contributing to HEV-associated fulminant hepatic failure. In aim 1, we will determine the effect and mechanism of pregnancy-associated sex hormones on HEV replication in human liver cells. We hypothesize that HEV infection inhibits the expression of estrogen receptor ER-α and ER-β during pregnancy, which results in suppression of host innate immunity leading to enhanced HEV replication. The effect of E1, E2 and P4, singly or in combination, on HEV replication in liver cells will be determined, and the underlying mechanisms of sex hormones in regulating HEV replication through the expression of estrogen receptor ER-α/ER-β, and progesterone receptor PGRMC1/PGRMC2 and their effect on cytokine expressions will be delineated. In aim 2, we will elucidate the role and mechanism of pregnancy-associated sex hormones in the development of fulminant hepatitis using a rabbit model. We hypothesize that changes of pregnancy-associated sex hormones suppress host innate and cell-mediated immune responses leading to enhanced HEV replication and fulminant hepatitis. Pregnant rabbits will be infected with HEV to identify the sex hormones and immunological correlates in the development of fulminant hepatitis during pregnancy. The mechanisms of P4- and E1/E2-mediated fulminant hepatitis will be delineated by quantifying mRNA and protein expression levels of ER-α/ER-β, PGRMC1/PGRMC2, and progesterone-induced blocking factor in liver and placenta tissues, and their effect on cytokine expressions in infected rabbits. In aim 3, we will define the viral genetic element(s) associated with fulminant hepatic failure. From case studies, 8 unique amino acid residues within HEV ORF1 are associated with fulminant hepatic failure. We hypothesize that these mutations significantly enhance HEV replication leading to higher viral loads and fulminant hepatic failure. We will first utilize HEV luciferase replicons to determine the effect of the 8 amino acid mutations on HEV replication in liver cells. The top 2 mutations with greatest enhancement on HEV replication will be introduced, singly and in combination, into genotype 3 HEV infectious clones to rescue mutant viruses, which will be used to infect pregnant rabbits to determine whether the identified mutations contribute to fulminant hepatitis. We anticipate to identify the sex hormone(s), underlying mechanisms, immunological correlates, and viral genetic element(s) contributing to the development of fulminant hepatic failure during HEV infection.
项目摘要:全球每年有2000万人感染戊型肝炎病毒(HEV),导致44,000人死亡 与HEV相关的肝胆疾病。HEV感染的一个独特特征是暴发型肝炎,死亡率高达25% 在孕妇身上。由于缺乏动物模型,HEV相关性致病的潜在机制 妊娠期暴发性肝炎尚不清楚。孕激素和雌激素等性激素水平的升高 已知在怀孕期间会促进某些病毒的复制,包括HEV。越来越多的证据表明 HEV的复制依赖于性激素,因为在性激素存在的情况下HEV的复制显著增强 或感染细胞中的妊娠血清。最近在兔身上发现了戊型肝炎病毒,这导致了妊娠模型的发展 对于HEV,由于高死亡率的暴发性肝炎在HEV感染中被令人信服和独立地复制 怀孕的兔子。长期目标是确定宿主(荷尔蒙和免疫)和病毒因素 与HEV相关的暴发性肝功能衰竭有关。在目标1中,我们将确定与妊娠相关的作用和机制。 性激素对人肝细胞中HEV复制的影响。我们假设戊型肝炎病毒感染抑制了 雌激素受体ER-α和ER-β在妊娠期间导致宿主天然免疫抑制导致 增强的HEV复制。E1、E2和P4单独或联合使用对HEV在肝细胞中复制的影响将是 已确定的,性激素通过表达HEV基因调控HEV复制的潜在机制 雌激素受体ER-α/ER-β和孕激素受体PGRMC1/PGRMC2及其对细胞因子表达的影响 被描绘出来。在目标2中,我们将阐明妊娠相关性激素在发育中的作用和机制。 使用兔模型进行暴发性肝炎的研究。我们假设妊娠相关性激素的变化抑制了 宿主的先天和细胞免疫反应导致HEV复制增强和暴发型肝炎。怀孕了 将戊型肝炎病毒感染兔,以确定性激素和免疫学相关因素在兔肝炎发展中的作用 妊娠期暴发性肝炎。P4和E_1/E_2介导的重型肝炎的机制将被阐明 通过定量ER-α/ER-β、PGRMC1/PGRMC2和孕酮诱导的基因和蛋白表达水平 肝脏和胎盘组织中的阻断因子及其对感染兔细胞因子表达的影响。在《目标3》中,我们将 定义与暴发性肝衰竭相关的病毒遗传因素(S)。从案例研究来看,8种独特的氨基酸残基 在HEV中,ORF1与暴发性肝衰竭相关。我们假设这些突变显著增强了 HEV复制导致更高的病毒载量和暴发性肝功能衰竭。我们将首先利用HEV荧光素酶复制子 探讨8个氨基酸突变对HEV在肝细胞中复制的影响。最大的两个突变 对HEV复制的增强将单独和组合引入到3型HEV感染性克隆中,以 拯救突变病毒,它将被用来感染怀孕的兔子,以确定已识别的突变是否起作用 到暴发性肝炎。我们期望确定性激素(S),潜在的机制,免疫学相关, 以及病毒遗传因素(S)在HEV感染过程中导致暴发性肝功能衰竭。

项目成果

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XIANG-JIN MENG其他文献

XIANG-JIN MENG的其他文献

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{{ truncateString('XIANG-JIN MENG', 18)}}的其他基金

Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    10022030
  • 财政年份:
    2020
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    10641790
  • 财政年份:
    2020
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    10206286
  • 财政年份:
    2020
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    10442715
  • 财政年份:
    2020
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    8444400
  • 财政年份:
    2012
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    8613516
  • 财政年份:
    2012
  • 资助金额:
    $ 39.3万
  • 项目类别:
Animal Model Research for Veterinarians (AMRV)
兽医动物模型研究 (AMRV)
  • 批准号:
    8267922
  • 财政年份:
    2012
  • 资助金额:
    $ 39.3万
  • 项目类别:
Mechanism of Hepatitis E Virus Replication and Pathogenesis
戊型肝炎病毒复制和发病机制
  • 批准号:
    9088272
  • 财政年份:
    2008
  • 资助金额:
    $ 39.3万
  • 项目类别:
Mechanism of Hepatitis E Virus Replication and Pathogenesis
戊型肝炎病毒复制和发病机制
  • 批准号:
    7575762
  • 财政年份:
    2008
  • 资助金额:
    $ 39.3万
  • 项目类别:
Mechanism of Hepatitis E Virus Replication and Pathogenesis
戊型肝炎病毒复制和发病机制
  • 批准号:
    8035437
  • 财政年份:
    2008
  • 资助金额:
    $ 39.3万
  • 项目类别:

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