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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：
9883580
负责人：
ROBERTO B. CATTANEO
金额：
$ 52万
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/9883580
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 Epithelium 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 Pharmacology Phase Process Property Proteins Recombinants Role SLAM protein Science Sensory Receptors Signal Transduction Sorting - Cell Movement Structure Structure of respiratory epithelium 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.

病毒学科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发病机制至关重要。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在上皮细胞内传播，从上皮细胞到神经元，主要是通过表达连接蛋白的感染细胞而不是通过病毒颗粒。在目标1中，我们将表征MeV在气道上皮细胞之间快速传播的机制。该假说是MeV选择锚定在其上皮受体nectin-4（N4）的胞质尾部的细胞骨架结构以快速扩散。在目标2和3中，我们专注于一种新的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，这是一种可以引发罕见但总是致命的疾病亚急性硬化性全脑炎（SSPE）的事件。我们发现，细胞质材料和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，我们将描述这种新过程的细胞生物学特征，我们将其命名为nectin-elucidated cytosine transfer（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，我们提出的证据表明，感染的N4表达上皮细胞可以转移MeV的神经元，而病毒颗粒不能。假设是NECT，而不是受体，负责MeV传递到神经元。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，为SSPE的下一阶段建模。