Complement-mediated Neutralization of Mumps Virus and SV5

补体介导的腮腺炎病毒和 SV5 的中和

• 批准号: 8069009
• 负责人: Griffith D. Parks
• 金额: $ 8.16万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-10 至 2011-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069009
• 关键词: Blocking Antibodies; Bypass; Cells; Complement; Complement Activation; Cytolysis; Data; Epithelial Cells; Glycoproteins; Goals; Human; Immune system; Infection; Maps; Mediating; Mumps virus; Outcome; Paramyxovirus; Pathway interactions; Population; Production; Proteins; RNA Interference; Recording of previous events; Refractory; Research; Resistance; Role; Signal Transduction; Simian virus 5; Surface; System; Testing; Up-Regulation; Vaccination; Viral; Virion; Virus; Virus-like particle; Work; base; bone; complement pathway; flexibility; innovation; interest; mutant; novel; novel therapeutics; novel virus; particle; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): This proposal is based on two remarkable findings from our lab. First, complement neutralizes the closely related paramyxoviruses Simian Virus 5 (SV5) and Mumps Virus (MuV), but by distinct mechanisms involving formation of massive SV5 aggregates versus complement mediated lysis of MuV particles. Secondly, our microarray data indicate that infection with the noncytopathic WT SV5 results in elevated levels of host cell regulators of complement and these virus-infected cells are not lysed by complement. Our long term goal of this project is to understand the cellular and viral factors that dictate the outcome of interactions of paramyxoviruses with complement. The short term goals are to 1) utilize a novel experimental system to identify viral signals that dictate the extent and pathway of complement neutralization and to 2) define the role of SV5-induced regulators of complement in preventing lysis of virus infected cells. An innovative aspect of our application is the use of SV5 and MuV virus-like particles (VLP) to analyze virus:complement interactions. This is a powerful and flexible system, in that novel VLPs that differ in viral components can be produced when these alterations would otherwise not be tolerated in the context of a bone fide infectious virus. In Aim 1, we will identify the cellular pathways and viral determinants involved in interactions of complement with SV5 and MuV virus-like particles (VLPs). The complement pathways and the viral determinants of complement activation will be identified through the use of VLPs that differ in their content of viral glycoproteins HN, F and SH. In Aim 2, we will test the hypothesis that SV5-infected epithelial cells are resistant to complement-mediate lysis due to upregulation of host cell regulators of complement. There is intense interest in defining mechanisms that modulate the interplay between viruses and the host innate immune system, but the role of complement in neutralization of paramyxoviruses is not completely understood. Our studies have important implications for understanding complement-mediated neutralization of viruses, the re-emergence in the human population of paramyxoviruses such MuV, and persistent infections, as well as great potential for exploiting the new information for novel therapeutic applications. PUBLIC HEALTH RELEVANCE: There is intense interest in defining mechanisms that modulate the interplay between viruses and the host innate immune system, but the role of complement in neutralization of paramyxoviruses is not completely understood. Our work will have important implications for control of viruses such as MuV, which has re-emerged despite wide-spread vaccination. In addition, our work with virus-induced inhibition of complement has implication for mechanisms by which viruses establish persistent infections that are refractory to recognition by host immune systems.

描述（由申请人提供）：该提案基于我们实验室的两项显着发现。首先，补体中和密切相关的副粘病毒猿猴病毒 5 (SV5) 和腮腺炎病毒 (MuV)，但通过不同的机制，涉及大量 SV5 聚集体的形成与补体介导的 MuV 颗粒裂解。其次，我们的微阵列数据表明，非细胞病变性WT SV5 的感染导致宿主细胞补体调节剂水平升高，并且这些病毒感染的细胞不会被补体裂解。我们该项目的长期目标是了解决定副粘病毒与补体相互作用结果的细胞和病毒因素。短期目标是 1) 利用新的实验系统来识别决定补体中和程度和途径的病毒信号，2) 确定 SV5 诱导的补体调节剂在防止病毒感染细胞裂解中的作用。我们应用的一个创新方面是使用 SV5 和 MuV 病毒样颗粒 (VLP) 来分析病毒：补体相互作用。这是一个强大而灵活的系统，因为病毒成分不同的新型 VLP 可以在真正的传染性病毒背景下无法容忍这些改变时产生。在目标 1 中，我们将确定补体与 SV5 和 MuV 病毒样颗粒 (VLP) 相互作用所涉及的细胞途径和病毒决定因素。将通过使用病毒糖蛋白 HN、F 和 SH 含量不同的 VLP 来鉴定补体途径和补体激活的病毒决定因素。在目标 2 中，我们将测试以下假设：由于补体的宿主细胞调节因子上调，SV5 感染的上皮细胞对补体介导的裂解具有抵抗力。人们对定义调节病毒与宿主先天免疫系统之间相互作用的机制有着浓厚的兴趣，但补体在中和副粘病毒中的作用尚不完全清楚。我们的研究对于理解补体介导的病毒中和、副粘病毒（如 MuV）在人群中的重新出现和持续感染具有重要意义，并且对于利用新信息进行新的治疗应用具有巨大的潜力。公共卫生相关性：人们对定义调节病毒与宿主先天免疫系统之间相互作用的机制非常感兴趣，但补体在中和副粘病毒中的作用尚未完全了解。我们的工作将对控制 MuV 等病毒产生重要影响，尽管广泛接种疫苗，但 MuV 仍重新出现。此外，我们对病毒诱导的补体抑制的研究对病毒建立难以被宿主免疫系统识别的持续感染的机制有影响。

项目成果

The paramyxoviruses simian virus 5 and mumps virus recruit host cell CD46 to evade complement-mediated neutralization.

副粘病毒、猿猴病毒 5 和腮腺炎病毒招募宿主细胞 CD46 来逃避补体介导的中和。

• 发表时间: 2009-08
• 作者: Johnson, John B;Grant, Ken;Parks, Griffith D
• 通讯作者: Parks, Griffith D