Towards Understanding the Morbidity of HEV Infection

描述（由申请人提供）：戊型肝炎（HEV）是肠道传播的RNA病毒，在许多欠发达国家（LDC）引起急性病毒性肝炎（AVH），经常报告孕妇发生暴发性肝炎。虽然HEV引起的AVH在美国不是地方性的，但在美国某些地区的献血者中，HEV抗体（抗HEV）的流行率高达20%。戊型肝炎是一种人畜共患疾病，有几种动物是其宿主。四种基因型的戊型肝炎病毒在血清学上具有交叉反应性，但具有不同的地理分布、种属特异性和毒力。但也有跨物种感染的报道。在印度次大陆，以及最近在巴格达的暴发和苏丹达尔富尔的难民中，从AVH病例中分离出了强毒的基因型1型HEV毒株。我们报告了HEV在埃及农村流行。尽管社区范围内抗-HEV流行率为70- 85%，但HEV引起的AVH很少见，在孕妇中未检测到暴发性HEV肝炎。然而，已经从开罗两名住院的AVH患者的粪便中分离出HEV基因型-1;并且HEV占住院埃及人AVH的10-30%。我们最近从埃及的家畜中分离出无毒基因型3型HEV（与美国发现的毒株相同）。我们的探索性发展奖的目的是准备，并获得初步数据，以测试可能解释为什么HEV引起的AVH可能是罕见的，在一些地区，如埃及和美国，尽管存在高抗HEV流行。其中包括：（1）先前早期暴露于HEV无毒毒株导致无症状或轻度感染，引发免疫，并在随后感染更强毒株期间抑制病毒血症和临床表现。(2)两种HEV基因型在埃及传播：（a）基因型3是地方性的，在动物宿主中人畜共患传播，引起人类无毒力感染;（B）毒力基因型1 HEV零星引起AVH。细胞介导的免疫（CMI）测试是必要的，以测试我们的假设;和HEV特异性CMI反应可能是一个长期的可靠的标记之前的暴露和/或保护随后的感染/发病率。目前还没有关于HEV CMI研究的报道，并且HEV毒株之间的血清学交叉反应性限制了抗HEV作为既往暴露于HEV无毒毒株的替代标志物的利用。因此，我们计划开发、标准化和使用可靠的测试来测量针对HEV毒株的独特表位的CMI应答。这将提供一种方法，以整理出病毒和宿主的免疫反应对埃及HEV传播和发病率的不同作用，结果将适用于其他地区，包括美国。因此，本申请将提供手段和初步数据，以设计一个协议，以了解参与HEV的发病机制的因素，作为一个重要的新兴传染病，似乎已经从动物传播到人。

DESCRIPTION (provided by applicant): Hepatitis E (HEV) is enterically transmitted RNA virus that causes acute viral hepatitis (AVH) in many lesser developed countries (LDC), with frequent reports of fulminant hepatitis in pregnant women. Although HEV- caused AVH is not endemic in the US, the prevalence of antibodies to HEV (anti-HEV) is as high as 20% among blood donors in certain areas of the US. HEV is a zoonotic disease with several animal species being reservoir hosts. The four genotypes of HEV are cross-reactive serologically but have different geographical distributions, species specificity, and virulence. However, cross-species infections have been reported. In the Indian subcontinent, and recently in outbreaks in Baghdad and in refugees in Darfur Sudan, the virulent genotype-1 strain of HEV was isolated from AVH cases. We reported HEV is endemic in rural villages in Egypt. In spite of community-wide anti-HEV prevalence of 70-85%, HEV-caused AVH was rare and fulminant HEV-hepatitis was not detected among pregnant women. However, HEV genotype-1 has been isolated from the stool of two hospitalized AVH patients in Cairo; and HEV has accounted for 10-to-30% of AVH in hospitalized Egyptians. We have recently isolated avirulent genotype-3 HEV (the same strain found in the US) from domestic animals in Egypt. Our exploratory development award's purpose is to prepare, and obtain preliminary data, to test hypotheses that may explain why HEV-caused AVH may be rare in some areas, like Egypt and the US, despite the presence of high anti-HEV prevalence. Among these are: (1) Prior early exposures to avirulent strains of HEV lead to asymptomatic or mild infections, prime immunity, and suppress viremia and clinical manifestations during subsequent infections with more virulent strains. (2) Two HEV genotypes are transmitted in Egypt: (a) genotype 3 is endemic and zoonotically transmitted among animal reservoirs causing avirulent infections in humans; and (b) the virulent genotype-1 HEV sporadically causes AVH. Cell-mediated immune (CMI) testing is necessary to test our hypotheses; and HEV-specific CMI responses may be a long-lasting reliable marker of prior exposure and/or protection to subsequent infection/morbidity. There are no reported HEV CMI studies, and the serological cross-reactivity among HEV strains, limits utilization of anti-HEV as surrogate markers for prior exposure to avirulent strains of HEV. Therefore, we plan to develop, standardize and use reliable tests to measure CMI responses against unique epitopes for HEV strains. This will provide the means to sort-out the different roles the virus and the host's immune response have on transmission and morbidity of HEV in Egypt, and the results would be applicable to other areas, including the US. Consequently, this application will provide the means and preliminary data to design a protocol to understand the factors involved in the pathogenesis of HEV, as one of the important emerging infectious diseases that appears to have spread from animals to man.