How does Cytomegalovirus use interferon lambda for optimal spread

巨细胞病毒如何利用 lambda 干扰素实现最佳传播

• 批准号: 10552002
• 负责人: Christopher C Norbury
• 金额: $ 20.3万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552002
• 关键词: Animal Model; Antiviral Response; Cells; Cellular Stress; Clinical; Complex; Cytomegalovirus; Cytomegalovirus Infections; DNA Viruses; Data; Dedications; Disease; Ensure; Environment; Epithelial Cells; Event; Fibroblasts; Gene Expression; Genes; Genetic Polymorphism; Genome; Geographic Locations; Human; Immune; Immune response; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Influenza; Innate Immune Response; Interferon Type II; Interferon-beta; Interferons; Kidney Transplantation; Ligands; Location; Mediating; Mediator; Molecular; Molecular Target; Mus; Organ; Pathogenesis; Pathologic; Pathway interactions; Phosphotransferases; Poxviridae; Predisposition; Pregnant Women; Process; Production; Productivity; Property; Protein Biosynthesis; Proteins; Proteome; Refractory; Role; Signal Pathway; Signal Transduction; Simplexvirus; Source; System; Therapeutic Intervention; Tissues; Viral; Virus; Virus Diseases; Virus Replication; West Nile virus; Wild Type Mouse; Work; adaptive immune response; antiviral immunity; arm; blocking factor; cell type; cellular targeting; clinically relevant; combat; design; differential expression; experimental study; gene product; genetic manipulation; human imaging; in vivo; inhibitor; lipid biosynthesis; mouse model; novel; receptor; response; sensor; socioeconomics; viperin

Project Summary Although largely asymptomatic, human cytomegalovirus (HCMV) can cause severe and even fatal disease in a subset of susceptible individuals. The large genome of HCMV allows it to devote a number of its gene products to optimizing conditions for replication in the host cell and combat cellular stress and antiviral responses. In some cases, HCMV even exploits these responses to promote infection. The host interferon system, consisting of Type I (T1, a, b, e, k, w), II (T2, g) and III (T3, l 1-4) interferons, has evolved to mediate innate antiviral immunity. However, we found that treatment with Type III interferons, which antiviral effects against a number of viruses including influenza and West Nile viruses, actually enhances the spread of HCMV in both fibroblasts and epithelial cells. These in vitro results were confirmed using an animal model for cytomegalovirus. Lower levels of MCMV infection were detected in several organs of mice lacking the IFN-l receptor when compared to wildtype mouse, confirming a role for IFN-l in promoting cytomegalovirus infection and spread. The experiments in this proposal will define the mechanism for IFN-l-dependent enhancement of cytomegalovirus infection using both in vitro and in vivo systems. This will be done in two specific aims. The first aim will define the pathways involved in proviral IFN-l signaling and how they differ from those that confer an antiviral environment. The second aim will delineate the properties of IFN-l during in vivo infection, including defining the cellular source of IFN-l production and identifying the cellular and molecular IFN-l-targets that mediate the proviral effect. Overall, these studies will define the mechanism by which cytomegaloviruses utilize a normally antiviral signaling response to enhance spread. These results will provide the basis for additional studies investigating the potential for therapeutic intervention of this clinically relevant process.

项目摘要 虽然在很大程度上无症状，但人巨细胞病毒（HCMV）可在感染者中引起严重甚至致命的疾病。 易感个体的子集。HCMV的大基因组使其能够将其许多基因产物 涉及优化宿主细胞中复制的条件以及对抗细胞应激和抗病毒应答。在 在某些情况下，HCMV甚至利用这些反应来促进感染。宿主干扰素系统，包括 I型（T1，a，B，e，k，w），II型（T2，g）和III型（T3，11 -4）干扰素的一部分，已经进化为介导先天性抗病毒 免疫力然而，我们发现，III型干扰素治疗，其中抗病毒作用对一些 包括流感病毒和西尼罗河病毒在内的病毒，实际上增强了HCMV在成纤维细胞中的传播， 和上皮细胞。使用巨细胞病毒的动物模型证实了这些体外结果。低 比较时，在缺乏IFN-I受体的小鼠的几个器官中检测到MCMV感染水平 野生型小鼠，证实了IFN-1在促进巨细胞病毒感染和扩散中的作用。的 本建议中的实验将确定IFN-1依赖性增强巨细胞病毒的机制 使用体外和体内系统进行感染。这将在两个具体目标下进行。第一个目标将定义 参与前病毒IFN-1信号传导的途径以及它们与赋予抗病毒活性的途径的区别 环境第二个目的将描述IFN-1在体内感染期间的性质，包括定义IFN-1在体内感染中的作用。 IFN-1产生的细胞来源和鉴定介导IFN-1产生的细胞和分子IFN-1靶 前病毒效应总的来说，这些研究将确定巨细胞病毒利用一种 正常的抗病毒信号反应，以加强传播。这些结果将为进一步的研究提供基础。 研究调查这种临床相关过程的治疗干预潜力。