Membrane Hijacking: Biogenesis and Fate of Quasi-Enveloped Hepatovirus

膜劫持:准包膜肝病毒的生物发生和命运

基本信息

  • 批准号:
    10223138
  • 负责人:
  • 金额:
    $ 38.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-24 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT ABSTRACT Hepatitis A virus (HAV), a member of the Picornaviridae (genus Hepatovirus), is an ancient human pathogen and a common cause of enterically-transmitted viral hepatitis globally. Long considered `nonenveloped', we discovered that HAV is released noncytolytically from infected cells both in vitro and in infected humans in vivo within extracellular vesicles that are similar in size and buoyant density to exosomes. The HAV capsid is completely cloaked by the membranes of these small vesicles, which nonetheless possess specific infectivity indistinguishable from naked HAV virions. The goal of this grant is to elucidate mechanisms underlying the biogenesis of these `quasi-enveloped' HAV (eHAV) virions and their role in the pathogenesis of hepatitis A. Extensive proteomics, virologic, and biophysical characterization of eHAV produced in cell culture demonstrate that viral capsids are selected for export in eHAV vesicles via a highly specific sorting process that is dependent on sequence in the pX domain of the VP1 capsid protein. We hypothesize (1) that the quasi- envelopment of eHAV results from budding of assembled VP1pX-containing capsids into endosomes (multivesicular bodies) in an ESCRT-dependent process mediated by specific interactions of capsid proteins with ESCRT complexes and facilitated by NEDD4-family E3 ubiquitin ligases; and (2) that cell entry by eHAV differs from naked virions and occurs within late endosome-lysosomes where membranes are hydrolyzed by lysosomal enzymes, providing capsid access to an unknown cellular receptor. In Specific Aim 1, we will map interactions of ESCRT components with VP1pX and ascertain the functional importance of ESCRT-0 and -I components in CRISPR/Cas9 knockout cells. Specific Aim 2 will determine whether catalytic activity of NEDD4-family ligases is required for eHAV biogenesis and contributes to ubiquitylation of pX or other capsid protein domains, and ascertain the extent to which core components of noncanonical `secretory autophagy' are involved in nonlytic eHAV egress. Specific Aim 3 will contrast mechanisms of eHAV vs. HAV entry, including endocytosis and endocytic transport, and define tissue tropisms of eHAV vs. HAV. Results from in vitro studies will be validated in vivo using a novel murine model of human hepatitis A. The discovery of eHAV has profoundly altered our understanding of the pathogenesis of this hepatotropic human virus and has substantial ramifications for the biology of other noncytopathic `nonenveloped' viruses, making this research of broad relevance to the field of virology.
项目摘要

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biliary Secretion of Quasi-Enveloped Human Hepatitis A Virus.
  • DOI:
    10.1128/mbio.01998-16
  • 发表时间:
    2016-12-06
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Hirai-Yuki A;Hensley L;Whitmire JK;Lemon SM
  • 通讯作者:
    Lemon SM
Peek-a-boo: membrane hijacking and the pathogenesis of viral hepatitis.
  • DOI:
    10.1016/j.tim.2013.10.005
  • 发表时间:
    2014-02
  • 期刊:
  • 影响因子:
    15.9
  • 作者:
    Feng, Zongdi;Lemon, Stanley M.
  • 通讯作者:
    Lemon, Stanley M.
Reassessing immune control of hepatitis A virus.
  • DOI:
    10.1016/j.coviro.2015.01.003
  • 发表时间:
    2015-04
  • 期刊:
  • 影响因子:
    5.9
  • 作者:
    Walker, Christopher M.;Feng, Zongdi;Lemon, Stanley M.
  • 通讯作者:
    Lemon, Stanley M.
MAVS-dependent host species range and pathogenicity of human hepatitis A virus.
  • DOI:
    10.1126/science.aaf8325
  • 发表时间:
    2016-09-30
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hirai-Yuki A;Hensley L;McGivern DR;González-López O;Das A;Feng H;Sun L;Wilson JE;Hu F;Feng Z;Lovell W;Misumi I;Ting JP;Montgomery S;Cullen J;Whitmire JK;Lemon SM
  • 通讯作者:
    Lemon SM
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Stanley M. Lemon其他文献

Hepatitis Viruses
  • DOI:
    10.1007/978-1-4615-0881-6
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Stanley M. Lemon
  • 通讯作者:
    Stanley M. Lemon
A simple method for clonal selection of hepatitis A virus based on recovery of virus from radioimmunofocus overlays.
一种基于从放射免疫聚焦覆盖物中回收病毒的甲型肝炎病毒克隆选择的简单方法。
  • DOI:
    10.1016/0166-0934(85)90040-0
  • 发表时间:
    1985
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Stanley M. Lemon;Robert W. Jansen
  • 通讯作者:
    Robert W. Jansen
Ins and outs of picornaviruses
小 RNA 病毒的来龙去脉
  • DOI:
    10.1038/nature21116
  • 发表时间:
    2017-01-11
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Kevin L. McKnight;Stanley M. Lemon
  • 通讯作者:
    Stanley M. Lemon
7. mRNA for selenoprotein P, a hepatokine, binds RIG-I protein and inhibits the RIG-I-mediated type I interferon response
7. 硒蛋白 P(一种肝因子)的 mRNA 结合 RIG-I 蛋白并抑制 RIG-I 介导的 I 型干扰素反应
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kazuhisa Murai;Masao Honda;Tetsuro Shimakami;Takayoshi Shirasaki;Hirofumi Misu;Toshinari Takamura;Stanley M. Lemon;Seishi Murakami;Shuichi Kaneko
  • 通讯作者:
    Shuichi Kaneko
Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome
整合素β1通过回收内体促进非包膜戊型肝炎病毒进入细胞
  • DOI:
    10.1038/s41467-025-61071-y
  • 发表时间:
    2025-06-26
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Rebecca Fu;Paula Jordan;Zoe Engels;Jasmin Alara Weihs;Josias Mürle;Huanting Chi;Sebastian Burbano de Lara;Barbara Helm;Mara Klöhn;Jungen Hu;Andrew Freistaedter;Tobias Boettler;Marco Binder;Ursula Klingmüller;Eike Steinmann;Pierre-Yves Lozach;Thibault Tubiana;Stanley M. Lemon;Viet Loan Dao Thi
  • 通讯作者:
    Viet Loan Dao Thi

Stanley M. Lemon的其他文献

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{{ truncateString('Stanley M. Lemon', 18)}}的其他基金

Critical Lipid Species in the Hepatovirus Lifecycle
肝病毒生命周期中的关键脂质种类
  • 批准号:
    10306348
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Critical Lipid Species in the Hepatovirus Lifecycle
肝病毒生命周期中的关键脂质种类
  • 批准号:
    10530593
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Critical Lipid Species in the Hepatovirus Lifecycle
肝病毒生命周期中的关键脂质种类
  • 批准号:
    9913862
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Novel Pathogen Recognition Pathways and Control of Hepatitis A Virus
新的病原体识别途径和甲型肝炎病毒的控制
  • 批准号:
    9233911
  • 财政年份:
    2014
  • 资助金额:
    $ 38.88万
  • 项目类别:
Membrane Hijacking: Biogenesis and Fate of Enveloped Hepatovirus
膜劫持:包膜肝病毒的生物发生和命运
  • 批准号:
    8549949
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
Membrane Hijacking: Biogenesis and Fate of Quasi-Enveloped Hepatovirus
膜劫持:准包膜肝病毒的生物发生和命运
  • 批准号:
    9764230
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
Murine Model of HCV-Associated Human Liver Cancer
HCV 相关人类肝癌的小鼠模型
  • 批准号:
    8625280
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
Murine Model of HCV-Associated Human Liver Cancer
HCV 相关人类肝癌小鼠模型
  • 批准号:
    8219397
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
Membrane Hijacking: Biogenesis and Fate of Enveloped Hepatovirus
膜劫持:包膜肝病毒的生物发生和命运
  • 批准号:
    8420039
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
Murine Model of HCV-Associated Human Liver Cancer
HCV 相关人类肝癌小鼠模型
  • 批准号:
    8464678
  • 财政年份:
    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
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