Intercellular transfer of cytoplasm and measles virus through nectins

病毒学传统上依赖于颗粒的分离和提纯，但病毒的细胞间传播可能是致病机制的关键。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在上皮细胞内传播，并从上皮细胞传播到神经元，主要通过表达蜜胶的受感染细胞发生，而不是通过病毒颗粒。在目标1中，我们将描述甲型肝炎病毒在呼吸道上皮细胞之间快速传播的机制。假设是MeV将细胞骨架结构锚定在其上皮受体Nectin-4(N4)的细胞质尾部，以迅速传播。在目标2和目标3中，我们专注于一种新的粘连蛋白依赖过程，该过程可能解释MeV感染如何在不需要神经受体的情况下到达神经元，这一事件可以启动罕见但始终致命的亚急性硬化性泛脑炎(SSPE)。我们发现胞质物质和MeV核糖核衣壳从表达N4的细胞转移到表达Nextin-1的细胞，包括神经元。在目标2中，我们将描述这一新的过程的细胞生物学特征，我们称之为Nextin诱导的细胞质转移(NECT)。假设包括病毒核糖核衣壳在内的NECT货物必须离开受体细胞的内吞途径才能发挥作用。在目标3中，我们提出了证据表明，感染的表达N4的上皮细胞可以将MeV转移到神经元，而病毒颗粒不能。假设是NECT，而不是受体，解释了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。

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.