The impact of quasi-envelopment on hepatitis virus infection and immunity

 描述(申请人提供)：甲型肝炎病毒(HAV)和戊型肝炎病毒(HEV)感染是世界欠发达地区流行性食源性和水源性肝炎的常见原因。最近，在发达国家，零星的HEV感染已成为一种重大的公共卫生危害。人畜共患病和通过血液传播的HEV及其在免疫抑制人群中的持续能力也令人担忧。大约20%的美国人口HEV血清阳性，这表明HEV接触比之前认为的更常见。尽管这两种病毒都被认为是无包膜的病毒，但最近的研究表明，甲型肝炎病毒和戊型肝炎病毒以“准包膜”粒子的形式在血液中循环。这些新型粒子与传统包膜病毒的不同之处在于，它们的膜表面不存在病毒抗原，因此对中和抗体具有高度抵抗力。这种“准包膜”对肝炎病毒生命周期、免疫和发病机制的影响还知之甚少。这项提议将探索准包膜甲型肝炎病毒和戊型肝炎病毒进入细胞并被抗体中和的机制。目的1将验证“准包膜”甲型肝炎病毒和戊型肝炎病毒是通过细胞外囊泡摄取的细胞机制进入的假设。目的2将确定准包膜甲型肝炎病毒和戊型肝炎病毒的中和机制。这些目标的完成将解决我们对准包膜病毒生命周期和致病机制理解中的几个最重大的差距。

 DESCRIPTION (provided by applicant): Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections are common causes of epidemic food-borne and water-borne hepatitis in under-developed regions of the world. Recently sporadic HEV infections have emerged as a significant public health hazard in well-developed countries. The recognition of zoonotic and blood-borne HEV transmission and its ability to persistent in immunosuppressed individuals is also alarming. Approximately 20% of the U.S. population is seropositive for HEV, indicating that HEV exposure is more common than previously thought. Although both recognized as non-enveloped viruses, recent studies show that HAV and HEV circulate in the blood as "quasi-enveloped" particles. These novel particles differ from classic enveloped viruses in that no viral antigens are present on the surface of their membrane, therefore are highly resistant to neutralizing antibodies. The impact of this "quasi-envelopment" on hepatitis virus life cycle, immunity, and pathogenesis is poorly understood. This proposal will explore the mechanisms by which quasi- enveloped HAV and HEV enter the cells and are neutralized by antibodies. Aim 1 will test the hypothesis that entry of "quasi-enveloped" HAV and HEV is through a cellular mechanism for extracellular vesicular uptake. Aim 2 will determine the mechanism of neutralization for quasi-enveloped HAV and HEV. Completion of these aims will address several of the most significant gaps in our understanding of the quasi-enveloped virus life cycle and pathogenesis.