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

基本信息

批准号：
10429668
负责人：
Nicholas J Buchkovich
金额：
$ 24.35万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-21 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10429668
关键词：
Animal Model Antiviral Response Cells Cellular Stress Response Clinical Complex Cytomegalovirus Cytomegalovirus Infections DNA Viruses Data Disease Ensure Environment Epithelial Cells Event Fibroblasts Gene Expression Genes Genetic Polymorphism Genome Geographic Locations Human Image Immune Immune response Immunocompromised Host In Vitro Incidence Individual Infection Influenza Interferon Type II Interferon-beta Interferons Kidney Transplantation Ligands Location Mediating Mediator of activation protein Molecular Molecular Target Mus Organ Pathogenesis Pathologic Pathway interactions Phosphotransferases Poxviridae Pregnant Women Process Production 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 in vivo inhibitor lipid biosynthesis mouse model novel receptor response sensor socioeconomics viperin

项目摘要

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.

项目概要尽管大部分无症状，但人类巨细胞病毒 (HCMV) 仍可导致严重甚至致命的疾病。易感个体的子集。 HCMV 庞大的基因组使其能够贡献大量基因产物优化宿主细胞中的复制条件并对抗细胞应激和抗病毒反应。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 (T2, g) 和 III (T3, l 1-4) 干扰素，已进化为介导先天抗病毒免疫。然而，我们发现用 III 型干扰素治疗，它对许多病毒有抗病毒作用。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 在两种成纤维细胞中的传播和上皮细胞。使用巨细胞病毒动物模型证实了这些体外结果。降低相比之下，在缺乏 IFN-1 受体的小鼠的几个器官中检测到 MCMV 感染水平对野生型小鼠进行研究，证实了 IFN-l 在促进巨细胞病毒感染和传播中的作用。这本提案中的实验将确定巨细胞病毒的 IFN-l 依赖性增强机制使用体外和体内系统进行感染。这将有两个具体目标来实现。第一个目标将定义参与前病毒 IFN-l 信号传导的途径以及它们与赋予抗病毒作用的途径有何不同环境。第二个目标将描述体内感染期间 IFN-l 的特性，包括定义 IFN-l 产生的细胞来源并鉴定介导的细胞和分子 IFN-l 靶标前病毒作用。总体而言，这些研究将确定巨细胞病毒利用通常抗病毒信号反应会增强传播。这些结果将为进一步的研究提供基础研究调查这一临床相关过程的治疗干预潜力。