Complement-mediated Neutralization of Mumps Virus and SV5

描述（由申请人提供）：本提案基于我们实验室的两个显著发现。首先，补体中和密切相关的副粘病毒类猴病毒5 （SV5）和腮腺炎病毒（MuV），但通过不同的机制，包括形成大量SV5聚集体和补体介导的MuV颗粒裂解。其次，我们的微阵列数据表明，非细胞病变WT SV5感染导致宿主细胞补体调节因子水平升高，这些病毒感染的细胞不会被补体溶解。我们这个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)利用一种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诱导的补体调节因子在防止病毒感染细胞裂解中的作用。我们的应用程序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，在这种情况下，当这些改变在骨性感染病毒的环境中不被容忍时，可以产生在病毒成分上不同的新型vlp。在目的1中，我们将确定补体与SV5和MuV病毒样颗粒（vlp）相互作用的细胞途径和病毒决定因素。补体途径和补体激活的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VLPs来确定。在Aim 2中，我们将验证sv5感染的上皮细胞由于宿主细胞补体调节因子的上调而对补体介导的溶解产生抗性的假设。人们对确定病毒与宿主先天免疫系统之间相互作用的调节机制有着浓厚的兴趣，但补体在中和副粘病毒中的作用尚未完全了解。我们的研究对于理解补体介导的病毒中和、在人群中重新出现的副粘病毒（如MuV）和持续感染具有重要意义，并且对于开发新的治疗应用具有巨大的潜力。公共卫生相关性：人们对确定病毒与宿主先天免疫系统之间相互作用的调节机制非常感兴趣，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等病毒具有重要意义，尽管广泛接种疫苗，但MuV仍再次出现。此外，我们在病毒诱导的补体抑制方面的工作也暗示了病毒建立宿主免疫系统难以识别的持续感染的机制。

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.