Intercellular transfer of cytoplasm and measles virus through nectins

通过连接蛋白进行细胞质和麻疹病毒的细胞间转移

基本信息

批准号：
10468967
负责人：
ROBERTO B. CATTANEO
金额：
$ 49.05万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468967
关键词：
Accounting Adherens Junction Alveolar Macrophages Axon Axonal Transport Binding Brain Cause of Death Cell Adhesion Molecules Cell membrane Cell physiology Cells Cellular biology Child Coculture Techniques Coupled Custom Cytoplasm Cytoplasmic Tail Cytoskeleton Cytosol Data Dendritic Cells Disease Endocytosis Epithelial Epithelial Cells Event Genetic Glycoproteins Human Immune Immunosuppression Infection Kinetics Lymphatic Lymphoid Tissue Measles Measles virus Mediating Membrane Membrane Fusion Microscopy Modeling Mutation Names Neurons Oranges Organ PVRL1 Pathogenesis Pathway interactions Persons Pharmacology Phase Process Property Proteins Recombinants Role SLAM protein Science Sensory Receptors Signal Transduction Sorting - Cell Movement Structure Subacute Sclerosing Panencephalitis System Testing Tight Junctions Time Vaccination Viral Viral Genome Viral Hemagglutinins Virion Virus Virus Diseases Virus Receptors airway epithelium base contagion design extracellular immune function innovation lymph nodes macrophage nectin novel particle primary lymphoid organ receptor relating to nervous system secondary infection transmission process viral transmission virology virus tropism

项目摘要

The science of virology traditionally relies on the isolation and purification of particles, but cell-to-cell transmission of viruses can be crucial for pathogenesis. For example, the entire lymphatic phase of measles virus (MeV) infection depends on intercellular transmission. Our central hypothesis is that MeV spread within epithelia, and from epithelia to neurons, occurs mainly through infected cells that express nectins, rather than through viral particles. In aim 1 we will characterize the mechanisms of rapid MeV spread between airway epithelial cells. The hypothesis is that MeV co-opts cytoskeletal structures anchored to the cytoplasmic tail of its epithelial receptor nectin-4 (N4) to spread rapidly. In aims 2 and 3 we focus on a novel nectin-dependent process that may explain how, without needing a neural receptor, MeV infections reach neurons, an event that can prime the rare but always-lethal disease subacute sclerosing panencephalitis (SSPE). We discovered that cytoplasmic materials and MeV ribonucleocapsids are transferred from cells expressing N4 to cells expressing nectin-1, including neurons. In aim 2 we will characterize the cell biology of this novel process that we named nectin-elicited cytoplasm transfer (NECT). The hypothesis is that NECT cargo, including viral ribonucleocapsids, has to exit the endocytic pathway of acceptor cells to become functional. In aim 3 we present evidence that infected N4-expressing epithelial cells can transfer MeV to neurons, while viral particles cannot. The hypothesis is that NECT, rather than a receptor, accounts for MeV delivery to neurons. We also use the primary neuron culture system to characterize the genetic basis for MeV spread, modeling the next phase of SSPE.

病毒学传统上依赖于颗粒的分离和纯化，但病毒的细胞间传播对于发病机制至关重要。例如，麻疹病毒（MeV）感染的整个淋巴阶段依赖于细胞间传播。我们的中心假设是，MeV 在上皮细胞内以及从上皮细胞到神经元的传播主要通过表达 nectin 的受感染细胞而不是通过病毒颗粒发生。在目标 1 中，我们将描述气道上皮细胞之间 MeV 快速传播的机制。假设 MeV 会选择锚定在其上皮受体 nectin-4 (N4) 细胞质尾部的细胞骨架结构来快速传播。在目标 2 和 3 中，我们重点关注一种新的 nectin 依赖性过程，该过程可以解释 MeV 感染如何在不需要神经受体的情况下到达神经元，这一事件可以引发罕见但始终致命的疾病亚急性硬化性全脑炎（SSPE）。我们发现细胞质物质和 MeV 核糖核衣壳从表达 N4 的细胞转移到表达 nectin-1 的细胞（包括神经元）。在目标 2 中，我们将描述这一新过程的细胞生物学特征，我们将其命名为 nectin 诱导的细胞质转移 (NECT)。假设是 NECT 货物，包括病毒核糖核衣壳，必须退出受体细胞的内吞途径才能发挥功能。在目标 3 中，我们提供的证据表明，受感染的表达 N4 的上皮细胞可以将 MeV 转移到神经元，而病毒颗粒则不能。假设是 NECT 而不是受体负责 MeV 向神经元的传递。我们还使用原代神经元培养系统来表征 MeV 传播的遗传基础，模拟 SSPE 的下一阶段。