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.

传统上，病毒学科学依赖于颗粒的隔离和纯化，但是病毒的细胞向细胞传播对于发病机理至关重要。例如，麻疹病毒（MEV）感染的整个淋巴阶段取决于细胞间传播。我们的中心假设是，MeV在上皮中扩散，从上皮到神经元，主要通过表达蜜饯而不是通过病毒颗粒的感染细胞发生。在AIM 1中，我们将表征气道上皮细胞之间快速MEV扩散的机制。假设是MeV相互作用的细胞骨架结构固定在其上皮受体Nectin-4（N4）的细胞质尾部以迅速扩散。在目标2和3中，我们专注于一种新型的依赖性蛋白依赖性过程，该过程可能解释了如何在不需要神经受体的情况下，MEV感染到达神经元，该事件可以促进罕见但始终致死的亚急性急性硬化性脑脑炎（SSPE）。我们发现细胞质材料和MEV核糖核糖剂从表达N4的细胞转移到表达nectin-1的细胞，包括神经元。在AIM 2中，我们将表征我们将其命名为nectin诱发的细胞质转移（NECT）的细胞生物学。假设是，包括病毒核糖核糖体内的矿货物必须退出受体细胞的内吞途径才能发挥功能。在AIM 3中，我们提供了证据表明，被感染的表达N4的上皮细胞可以将MEV转移到神经元中，而病毒颗粒不能将其转移到神经元中。假设是nect而不是受体解释了向神经元传递的MEV。我们还使用原发性神经元培养系统来表征MEV扩散的遗传基础，从而对SSPE的下一阶段进行建模。