Paramyxovirus Activation and Inhibition of Complement Pathways

描述（由申请方提供）：补体系统是所有动物病毒在自然感染期间遇到的先天免疫应答的关键组成部分。虽然很明显补体（C '）是中和许多RNA病毒的重要因素，但关于C'如何调节呼吸道中的副粘病毒感染和病理学的机制细节知之甚少。在这里，我们试图填补理解补体（C '）与副粘病毒猿猴病毒5（SV 5），腮腺炎病毒（MuV）和呼吸道合胞病毒（RSV）的相互作用的空白。 该项目源于最近的发现：1）C'在中和SV 5和MuV两者中起重要作用，2）SV 5和RSV诱导补体激活的细胞调节因子（RCA）的表达，并且一些RCA被掺入到SV 5、MuV和RSV病毒体中，以及3）在C'耗尽的小鼠的肺中增强SV 5生长，但鼻组织中的生长不受影响。我们的长期目标是了解决定副粘病毒与感染动物呼吸道中C'相互作用结果的细胞和病毒因素。 目的1将确定RCAs掺入SV 5、MuV和RSV病毒粒子的机制以及病毒粒子相关的RCAs在体内中和和病理学中的作用。这将涉及使用创新的EM方法、VLP和过表达RCA的新型病毒。目标2中的工作将定义SV 5、MuV和RSV差异上调RCA表达的机制以及感染细胞如何免于裂解。我们的研究结果表明，SV 5的生长在肺中增强，但不是在C '-耗尽小鼠的鼻组织中。在目的3中，我们将使用遗传缺陷小鼠来区分C'在SV 5和RSV中和中的直接作用与C'在免疫细胞向组织的差异募集中的作用。 我们工作中出现的新概念涉及以下问题：1）单个RCA如何有助于呼吸道中的病毒清除和发病机制，2）什么信号指导RCA掺入出芽颗粒，3）副粘病毒利用什么信号传导途径使细胞对C '-介导的裂解具有抗性，以及4）什么机制决定了C'在限制感染动物肺中而不是鼻组织中的病毒载量方面的不同作用。解决这些概念将对我们理解对病毒的先天免疫这一未充分研究的领域产生重大影响。 公共卫生相关性：人们对调节病毒和宿主先天免疫系统之间相互作用的机制非常感兴趣，但补体在中和呼吸道病毒中的作用的机制细节尚不清楚。我们的工作将对人类病原体如MuV和RSV的控制产生重要影响。副粘病毒抑制补体的见解将有影响的发病机制，疫苗开发，和持久性感染，难以识别的宿主免疫系统。

DESCRIPTION (provided by applicant): The complement system is a critical component of the innate immune response that all animal viruses encounter during natural infections. While it is clear that complement (C') is an important factor in neutralization of many RNA viruses, very few mechanistic details are known about how C' regulates paramyxovirus infections and pathology in the respiratory tract. Here, we seek to fill gaps in understanding of interactions of complement (C') with the paramyxoviruses Simian Virus 5 (SV5), Mumps virus (MuV) and Respiratory Syncytial Virus (RSV). This project emerged from recent findings that: 1) C' plays an essential role in neutralization of both SV5 and MuV, 2) SV5 and RSV induce expression of cellular Regulators of Complement Activation (RCA) and some RCAs are incorporated into SV5, MuV and RSV virions, and 3) SV5 growth is enhanced in lungs of C'-depleted mice, but growth in the nasal tissue is not affected. Our long term goal is to understand the cellular and viral factors that dictate the outcome of interactions of paramyxoviruses with C' in the respiratory tract of infected animals. Aim 1 will determine the mechanism of incorporation of RCAs into SV5, MuV and RSV virions and the role of virion-associated RCAs in neutralization and pathology in vivo. This will involve the use of an innovative EM approach, VLPs, and novel viruses that overexpress RCAs. Work in Aim 2 will define the mechanisms by which SV5, MuV and RSV differentially upregulate RCA expression and how infected cells are spared from lysis. Our results show that SV5 growth is enhanced in the lung but not the nasal tissue of C'-depleted mice. In Aim 3 we will use genetically deficient mice to distinguish between a direct role for C' in SV5 and RSV neutralization versus a role for C' in differential recruitment of immune cells to tissues. New concepts that have emerged from our work address the questions of: 1) how individual RCAs contribute to viral clearance and pathogenesis in the respiratory tract, 2) what signals direct RCA incorporation into budding particles, 3) what signaling pathways are exploited by paramyxoviruses to make cells resistant to C'-mediated lysis, and 4) what mechanisms dictate differential roles for C' in limiting viral load in the lung but not in the nasal tissue of infected animals. Addressing these concepts will have a significant impact on our understanding of this understudied area of innate immunity to viruses. PUBLIC HEALTH RELEVANCE: There is intense interest in mechanisms that modulate the interplay between viruses and the host innate immune system, but the mechanistic details on the role of complement in neutralization of respiratory tract viruses are not known. Our work will have important impact on control of human pathogens such as MuV and RSV. Insights into paramyxovirus inhibition of complement will have implications for pathogenesis, vaccine development, and persistent infections that are refractory to recognition by host immune systems.