Role of a secreted form of ORF2 protein in hepatitis E virus infection

分泌型 ORF2 蛋白在戊型肝炎病毒感染中的作用

基本信息

批准号：
10196193
负责人：
Zongdi Feng
金额：
$ 23.1万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-08 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196193
关键词：
Acute Hepatitis Animal Model Antibodies Antibody Response Antibody Therapy Capsid Capsid Proteins Cell Line Cells Chronic Hepatitis Codon Nucleotides Cytoplasmic Protein Data Disease Effectiveness Enteral Exhibits Genome Goals Hepatitis E virus Human Immune Evasion Immune system Immunity Immunocompromised Host Immunologics Individual Infection Initiator Codon Lead Life Cycle Stages Light Liver Liver Cirrhosis Liver diseases Macaca Mediating Modeling Monoclonal Antibodies Mus Mutagenesis Nucleotides Nude Rats ORF2 protein Open Reading Frames Outcome Pathogenesis Pathway interactions Patients Peptide Signal Sequences Phase Plasma Play Process Proteins Publishing RNA RNA Viruses RNA replication Rattus Reading Frames Reporting Risk Role Sequence Homology Serum Small RNA Study models System Therapeutic Translating Translations Viral Viral Pathogenesis Virion Virus Virus Diseases Virus Replication Work base cross reactivity cross-species transmission dimer hepatoma cell improved in vivo in vivo evaluation inhibiting antibody insight neutralizing antibody novel particle reverse genetics targeted treatment viral RNA

项目摘要

Abstract The enterically transmitted hepatitis E virus (HEV) infects ~20 million people annually. HEV infection is usually self-resolving but can persist in individuals with a weakened immune system and result in fast progression into liver cirrhosis. HEV encodes a single capsid protein ORF2. Nonetheless, recent studies show that most ORF2 proteins released from HEV-infected cells are not associated with virus particles. The exact role(s) of the secreted ORF2 (ORF2s) plays is poorly understood, which hampers our understanding of HEV infection and pathogenesis. Our recently published work demonstrated that ORF2s and the capsid are two different translation products. A signal sequence unique to ORF2s directs its secretion via the secretory pathway, where as a conserved, but previously unrecognized, internal start codon is responsible for translation of the capsid- associated ORF2 (ORF2c). We further found that ORF2s exists as a glycosylated dimer with substantial antigenic overlap with the virion, and purified ORF2s was able to inhibit antibody-mediated neutralization of HEV. Based on these data, we hypothesize that ORF2s acts as a decoy to evade the host antibody response during HEV infection. Our long-term goal is to better understand how ORF2s modulates HEV infection and host immunity and whether it contributes to pathogenesis. The objectives of this project are to use an established rat model to test the in vivo role(s) of ORF2s in HEV infection. Aim 1 will determine if eliminating ORF2s expression alters host antibody responses and the course of acute HEV infection. Aim 2 will determine if serum ORF2s interferes with antibody therapy of chronic HEV infection, and if so whether the effectiveness of antibody therapy will be improved by using antibodies that target ORF2c but not ORF2s. The concept that ORF2S functions as an immunological decoy is novel and may have important implications for HEV immune evasion and persistence. The expected outcomes will fill a significant gap in our understanding of the role of secreted ORF2 in the HEV life cycle and pathogenesis with the potential for more targeted therapies where no cure currently exists.

抽象的肠道传播的戊型肝炎病毒 (HEV) 每年感染约 2000 万人。 HEV 感染通常是可自行解决，但在免疫系统较弱的个体中可能持续存在，并导致快速进展为肝硬化。 HEV 编码单个衣壳蛋白 ORF2。尽管如此，最近的研究表明大多数 ORF2 HEV 感染细胞释放的蛋白质与病毒颗粒无关。的确切角色人们对分泌型 ORF2 (ORF2) 的作用知之甚少，这阻碍了我们对 HEV 感染和发病。我们最近发表的工作表明 ORF2 和衣壳是两种不同的翻译产品。 ORF2 特有的信号序列通过分泌途径指导其分泌，其中保守但以前未被识别的内部起始密码子负责衣壳的翻译相关的 ORF2 (ORF2c)。我们进一步发现ORF2作为糖基化二聚体存在，具有大量的与病毒粒子的抗原重叠，纯化的 ORF2 能够抑制抗体介导的 HEV 中和。基于这些数据，我们假设 ORF2 作为诱饵来逃避宿主抗体反应戊型肝炎病毒感染。我们的长期目标是更好地了解 ORF2 如何调节 HEV 感染和宿主免疫及其是否有助于发病。该项目的目标是使用已建立的大鼠模型来测试 ORF2 在 HEV 感染中的体内作用。目标 1 将确定是否消除 ORF2 表达改变宿主抗体反应和急性 HEV 感染的过程。目标 2 将确定血清 ORF2 是否干扰慢性 HEV 感染的抗体治疗，如果是，抗体治疗是否有效通过使用针对 ORF2c 但不针对 ORF2s 的抗体，将得到改善。 ORF2S 功能的概念免疫诱饵是新颖的，可能对 HEV 免疫逃避和持续存在具有重要意义。预期结果将填补我们对分泌型 ORF2 在 HEV 中的作用的理解上的重大空白生命周期和发病机制，有可能在目前尚无治愈方法的情况下进行更有针对性的治疗。