New Opportunities - Mechanisms of Early Vaccinia Viral Morphogensis

新机遇——早期牛痘病毒形态发生机制

• 批准号: 7680587
• 负责人: Stuart N. Isaacs
• 金额: $ 7.09万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680587
• 关键词: Biological; Biology; Bypass; Capsid Proteins; Categories; Coat Protein Complex I; Coatomer Protein; Collaborations; Complex; Family; Funding; Future; Golgi Apparatus; Head; Hospitals; Integration Host Factors; KDEL receptor; Ligands; Lysine; Membrane; Morphogenesis; Pennsylvania; Play; Poxviridae; Process; Proteins; Request for Applications; Research Personnel; Research Project Grants; Role; Shapes; Staging; Transport Vesicles; United States National Institutes of Health; Universities; Vaccines; Vaccinia; Vaccinia virus; Vesicle; Viral; Viral Proteins; Virus; Woman; abstracting; expression vector; insight; member; mutant; novel; pathogen; protein function; therapy design

Abstract Members of the poxvirus family have been investigated for their applications as vaccines and expression vectors, and more recently intently studied because of their use as potential biological weapons. Vaccinia virus, the prototypic member, evolves through multiple forms in acquiring infectivity, for which early membrane morphogenesis plays a key role. Even though viruses generally usurp host factors for its use, it remains unclear whether key host transport factors that are well known to act in membrane morphogenesis of cellular compartments participate in early vaccinia membrane morphogenesis. We have now discovered a role for coatomer, a host protein complex known to shape Coat Protein I (COP!) transport vesicles. However, insights into how coatomer participates in early viral morphogenesis reveals that the virus bypasses key regulatory mechanisms that form host COP1 vesicles, but instead its interaction with two proteins, the viral K7 and the host KDEL receptor (KDELR) through critical di-lysine residues is likely important. Thus, to gain further insight into how coatomer and its two interacting proteins contribute to viral replication, we propose two major aims. In one aim headed by Victor Hsu with proposed funding from NERCE, perturbation of coatomer will be examined for its effect in potentially accumulating particular viral forms. Moreover, the KDELR will be examined with respect to its distribution on viral forms and also whether its ligands have a role in viral replication. As another aim headed by Stuart lsaacs with proposed funding from MARCE, the viral K7 protein will be examine for effects upon its deletion and also when a mutant form that cannot interact with coatomer is expressed. This collaborative effort is responsive in multiple ways to the request for application under the "New Opportunities" initiative by the two respective Regional Centers of Excellence. First, we will be gaining insights into a Category A pathogen, for which we will not only elucidate novel mechanisms by which a host protein functions during viral replication, but also identify potential key target(s) for the future design of intervention against the most abundant infectious form of the virus. Second, funding of this proposal will allow one of the main investigators (Victor Hsu) to collaborate with a poxvirus expert (Stuart Isaacs), and thus, applying outside expertise in mechanisms of vesicular transport to critical issues in poxvirus biology. As viruses generally commandeer host mechanisms for their interaction with the host rather than inventing completely novel ones, the complementary expertise of the collaboration will likely enhance the elucidation of how vaccinia virus interacts with its host. Third, potential funding of this proposal will likely set the stage for an eventual more comprehensive application in the future, such as through the NIH R01 mechanism.

抽象的 Poxvirus家族的成员已被调查，因为他们的应用是疫苗和表达媒介，并且由于它们用作潜在的生物武器而被专心研究。原型成员Vaccinia病毒通过多种形式而发展，以获得感染性，对此，早期的膜形态发生起着关键作用。即使病毒通常占据宿主因素的使用，但仍不清楚众所周知，在细胞室的膜形态发生中众所周知的关键宿主转运因子是否参与了早期的疫苗膜形态发生。现在，我们发现了Coatomer的角色，Goatomer是一种宿主蛋白​​络合物，已知塑造涂层蛋白I（COP！）传输囊泡。然而，对外皮机如何参与早期病毒形态发生的见解表明，该病毒绕过形成宿主COP1囊泡的关键调节机制，而是与两个相互作用 蛋白质，病毒K7和宿主KDEL受体（KDELR）通过临界Di-Lysine残基很重要。因此，为了进一步了解涂层剂及其两种相互作用蛋白如何促进病毒复制，我们提出了两个主要目的。在一个由Victor hsu领导的一个目标中，Nerce的拟议资金将对面膜的扰动进行检查，以便对其在潜在地积累特定的病毒形式中的影响。此外，Kdelr将在病毒形式的分布以及是否是否 它的配体在病毒复制中起作用。作为由Stuart LSAACS领导的另​​一个目标，并向Marce提出了资金，病毒K7蛋白将检查其缺失的影响以及当表达无法与涂层物相互作用的突变体形式时。 这项协作努力以多种方式响应于两个各个地区卓越中心的“新机遇”倡议下的申请请求。首先，我们将获得对病原体类别的见解，为此，我们不仅会阐明宿主蛋白在病毒复制过程中起作用的新型机制，而且还确定了潜在的关键目标（S） 对最丰富的传染性形式的干预。其次，该提案的资金将允许一位主要的研究人员（Victor HSU）与Poxvirus Expert（Stuart Isaacs）合作，因此，将囊泡运输机制的外部专业知识应用于Poxvirus生物学的关键问题。作为病毒通常与主机互动而不是发明的指挥生主机机制 完全新颖的协作互补专业知识可能会增强疫苗病毒与宿主相互作用的方式的阐明。第三，该提案的潜在资金可能会为未来最终更全面的应用奠定基础，例如通过NIH R01机制。