Paramyxovirus Activation and Inhibition of Complement Pathways

副粘病毒激活和补体途径的抑制

• 批准号: 8897063
• 负责人: Griffith D. Parks
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897063
• 关键词: Address; Affect; Animal Viruses; Animals; Area; Cell Line; Cell surface; Cells; Complement; Complement 2; Complement Activation; Complement Inactivators; Complement Receptor; Cytolysis; Engineering; Face; Goals; Growth; Human; Immune; Immune response; Immune system; Individual; Infection; Lead; Lung; Mediating; Mumps virus; Mus; Natural Immunity; Nose; Outcome; Paramyxovirus; Pathogenesis; Pathology; Play; Publishing; RNA Viruses; Refractory; Resistance; Respiratory Syncytial Virus Infections; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Respiratory tract structure; Role; Signal Pathway; Signal Transduction; Simian virus 5; System; Tissues; Up-Regulation; Viral; Viral Load result; Virion; Virus; Virus Assembly; Virus-like particle; Work; complement pathway; complement system; in vivo; innovation; insight; interest; novel; novel virus; overexpression; particle; pathogen; prevent; recombinant virus; vaccine development

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.

描述（由申请人提供）：补体系统是所有动物病毒在自然感染过程中遇到的先天免疫反应的关键组成部分。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' 如何调节呼吸道副粘病毒感染和病理的机制细节却知之甚少。在这里，我们试图填补补体 (C') 与副粘病毒猴病毒 5 (SV5)、腮腺炎病毒 (MuV) 和呼吸道合胞病毒 (RSV) 相互作用的理解空白。 该项目源于最近的发现：1) C' 在 SV5 和 MuV 的中和中发挥重要作用，2) SV5 和 RSV 诱导细胞补体激活调节因子 (RCA) 的表达，并且一些 RCA 并入 SV5、MuV 和RSV 病毒体，以及 3) C' 耗尽小鼠的肺中 SV5 生长增强，但鼻组织中的生长不受影响。我们的长期目标是了解决定受感染动物呼吸道中副粘病毒与 C' 相互作用结果的细胞和病毒因素。 目标 1 将确定 RCA 掺入 SV5、MuV 和 RSV 病毒粒子的机制以及病毒粒子相关 RCA 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 和过度表达 RCA 的新型病毒。目标 2 中的工作将定义 SV5、MuV 和 RSV 差异上调 RCA 表达的机制，以及受感染的细胞如何避免裂解。我们的结果表明，C'-耗尽小鼠的肺组织中的 SV5 生长增强，但鼻组织中的生长没有增强。在目标 3 中，我们将使用遗传缺陷小鼠来区分 C' 在 SV5 和 RSV 中和中的直接作用与 C' 在免疫细胞向组织的差异招募中的作用。 我们的工作中出现的新概念解决了以下问题：1）单个 RCA 如何促进呼吸道中的病毒清除和发病机制，2）什么信号直接将 RCA 掺入出芽颗粒中，3）副粘病毒利用哪些信号通路来使细胞对 C' 介导的裂解具有抵抗力，以及 4) 哪些机制决定了 C' 在限制受感染动物的肺部病毒载量而不是鼻组织中的病毒载量方面发挥不同作用。解决这些概念将对我们对病毒先天免疫这一尚未研究的领域的理解产生重大影响。