Complement Resistance Acquired During Acute to Persistent Rubulavirus Infection

急性至持续性风疹病毒感染期间获得的补体耐药性

• 批准号: 10645486
• 负责人: Griffith D. Parks
• 金额: $ 24.12万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-23 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10645486
• 关键词: Acute; Air; Binding; Biochemical; Biological Assay; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Clinical; Clinical Trials; Complement; Complement Factor H; Complement Inactivators; Cytolysis; Data; Drug Modulation; Engineering; Environment; Epithelial Cells; Fibrinogen; Future; Genetic Polymorphism; Genome; Goals; Human; In Vitro; Infection; Inflammation; Innate Immune System; Liquid substance; Lung; Lung infections; Mediating; Mumps virus; Paramyxovirus; Pathway interactions; Population; Production; Proteomics; RNA Virus Infections; Resistance; Respiratory System; Respiratory Tract Infections; Role; Rubulavirus; Rubulavirus Infections; Severities; Surface; Testing; Therapeutic; Time; Trachea; Variant; Viral; Viral Respiratory Tract Infection; Virion; Virus; Virus Diseases; Virus Replication; Vitronectin; Work; acute infection; chronic infection; conditioning; gene complementation; inhibitor; innate immune mechanisms; innate immune pathways; interest; parainfluenza virus; pathogen; prototype; recruit; respiratory; respiratory infection virus; response; sulfated glycoprotein 2; transcriptomics

For many RNA virus infections, an initial acute infection can transition to a prolonged or persistent infection, in which infected cells survive and continue to produce progeny virus. Complement (C’) is a powerful innate immune system which can directly lyse virus-infected cells or neutralize virus (1-4), but the role of C’ in controlling persistent respiratory RNA virus infections is not well understood. Given that viruses have mechanisms to block C’-mediated cell lysis, persistent infections can set up a prolonged inflammation cycle – where activated C’ continues to provide damaging inflammation, but viral inhibitory mechanisms block elimination of pathogen and infected cells. This project emerged from our striking findings that during an initial acute infection of human lung cells with the Rubulavirus Parainfluenza virus 5 (PIV5), infected cells are very sensitive to C’-mediated lysis. Importantly however, after transitioning to a persistent infection, PIV5-infected cells are nearly completely resistant to C’ lysis. Our transcriptomics data show that PIV5 acutely infected cells have low level expression of C’ inhibitors, but this shifts to high level expression of cellular C’ inhibitors Factor H, Factor I, Vitronectin and Clusterin in persistently infected cells. Our central hypothesis is that PIV5 persistently infected cells acquire resistance to C’-mediated lysis due to their acquired ability to express high levels of C’ inhibitors Factor H and Vitronectin. Our goals are to identify: 1) the mechanisms for acquiring C’ resistance during the PIV5 acute-to-persistent transition (Aim 1), and 2) consequences of this shift for production of C’-resistant virus (Aim 2). Aim 1 will define the mechanism for differential sensitivity of airway cells to C’-mediated lysis during transition from acute to persistent infection. Engineered respiratory tract cell lines and primary tracheal or bronchial air-liquid interface (ALI) cell cultures will be used to test the hypothesis that synthesis of C’ inhibitors Factor H and Vitronectin by persistently infected cells results in conditioning of the cells to be resistant to C’-mediated lysis. Aim 2 will identify C’ factors associated with virus particles derived from acute versus persistently infected cells and define the sensitivity of persistent virus to C’- mediated neutralization. Proteomics and biochemical assays will test the hypothesis that virus derived from persistently infected cells will be C’-resistant due to recruitment of Factor H or Vitronectin. Results from our work on C’ interactions with persistent RNA virus infections will have strong potential to inform therapeutics, given: 1) the clinical impact of prolonged viral respiratory infections, 2) polymorphisms in C’ genes can correlate with severity of viral infections, and 3) clinical trials for respiratory tract infections are underway with drugs that modulate C’ responses.

对于许多 RNA 病毒感染，最初的急性感染可以转变为长期或持续的感染。 感染，其中受感染的细胞存活并继续产生子代病毒。 强大的先天免疫系统，可以直接裂解病毒感染的细胞或中和病毒(1-4)，但是 鉴于此，C' 在控制持续性呼吸道 RNA 病毒感染中的作用尚不清楚。 病毒具有阻止 C' 介导的细胞裂解的机制，持续感染可以建立长期的 炎症周期 – 激活的 C' 继续提供破坏性炎症，但病毒抑制 机制阻止病原体和受感染细胞的消除。 这个项目源于我们惊人的发现，即在人类肺部最初的急性感染期间 感染副流感病毒 5 (PIV5) 的细胞，受感染的细胞对 C' 介导非常敏感 然而重要的是，在转变为持续感染后，PIV5 感染的细胞几乎会发生裂解。 我们的转录组学数据表明，PIV5 急性感染细胞具有较低的抗性。 C'抑制剂的水平表达，但这转变为细胞C'抑制剂H因子的高水平表达， 持续感染细胞中的因子 I、玻连蛋白和簇蛋白。 我们的中心假设是PIV5持续感染的细胞获得了对C'介导的抗性 由于它们具有表达高水平 C' 抑制剂 H 因子和玻连蛋白的能力。 目标是确定：1​​) 在 PIV5 急性至持续期间获得 C’抗性的机制 转变（目标 1），以及 2）这种转变对 C' 抗性病毒产生的影响（目标 2）。 目标 1 将定义气道细胞对 C' 介导的裂解的不同敏感性的机制 从急性感染到持续感染的转变过程中。 气管或支气管气液界面（ALI）细胞培养物将用于检验以下假设： 持续感染的细胞合成 C' 抑制剂 H 因子和玻连蛋白，导致调节 目标 2 将识别与病毒颗粒相关的 C' 因子。 源自急性与持续感染细胞，并定义持续病毒对 C'- 的敏感性 介导的中和作用将检验病毒衍生的假设。 由于 H 因子或玻连蛋白的募集，持续感染的细胞将具有 C' 抗性。 我们关于 C' 与持续性 RNA 病毒感染相互作用的研究结果将具有很强的影响力。 考虑到以下因素，有可能为治疗提供信息：1) 长期病毒性呼吸道感染的临床影响，2) C’基因的多态性可能与病毒感染的严重程度相关，3) 临床试验 调节 C' 反应的药物正在引起呼吸道感染。