Intra- and Inter-Neuronal Viral Trafficking

神经元内和神经元间病毒贩运

• 批准号: 7627984
• 负责人: GLENN F RALL
• 金额: $ 38.17万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627984
• 关键词: Acute; Address; Adopted; Affect; Axon; Biochemical; Brain; CD46 Antigen; Cell Culture Techniques; Cell Line; Central Nervous System Diseases; Central Nervous System Infections; Central Nervous System Viral Diseases; Chimeric Proteins; Chronic; Chronic Disease; Cytopathology; Cytoskeleton; Diffusion; Dynein ATPase; Environment; F Protein Measles Virus; Family; Foundations; Genetic; Goals; Herpesviridae; Human; Impairment; Infection; Kinesin; Lead; Length; Life; Life Cycle Stages; Liquid substance; Measles; Measles virus; Microtubules; Molecular Motors; Motor; Movement; Mus; Neuraxis; Neurites; Neuroblastoma; Neurons; Neuropathogenesis; Neurotransmitter Receptor; Paramyxovirus; Pathogenesis; Poliomyelitis; Predisposition; Process; Production; Proteins; Rabies; Role; Site; Subacute Sclerosing Panencephalitis; Substance P; Substance P Receptor; Synapses; Synaptic Cleft; Synaptic Membranes; Synaptic Transmission; Testing; Transgenic Mice; Viral; Viral Proteins; Virion; Virus; Virus Diseases; env Gene Products; human trophoblast leucocyte common antigen; in vivo; inhibitor/antagonist; member; mouse model; nervous system disorder; neuron loss; neuronal cell body; neuronal transport; neurotransmission; neurotropic virus; novel; prevent; protein protein interaction; public health relevance; receptor; therapy development; trafficking; transmission process; viral RNA

DESCRIPTION (provided by applicant): Many neurotropic viruses are transmitted trans-synaptically, including measles, polio, rabies and some herpesviruses. Nevertheless, the viral protein-neuronal protein interactions that govern this process are not known. Moreover, while these viruses cause rapid, highly productive infections in the periphery, most are associated with chronic infections in the brain, likely due to reduced viral progeny production and cytopathology in neurons. Thus, the objectives of this proposal are to define how viruses, such as measles virus, interact with neuronal proteins to affect both intra- and inter-neuronal transport, and to establish how this mode of spread is associated with chronic central nervous system infections. These broad objectives will be accomplished through completion of two Specific Aims. In the first aim, intra-neuronal spread of measles virus to the synapse is studied, which will characterize the viral proteins that are present at synaptic membranes, and whether these proteins are required for trans-synaptic spread. In addition, interaction with cellular motor proteins that govern movement along microtubules will be determined. In the second aim, inter-neuronal measles transmission is addressed, and the role of a putative, novel fusion protein receptor, neurokinin-1, ascertained. Specifically, we will establish if neurokinin-1 is required for viral neurotransmission, whether the measles fusion protein and neurokinin-1 interact, and, ultimately, how blockade of this proposed interaction affects viral spread and pathogenesis in a susceptible transgenic mouse model. Successful completion of these aims will contribute to our long-term goals that include: (1) identification of cellular factors that contribute to viral persistence in neurons; (2) determination of how viral persistence may lead to host impairment without neuronal loss; and eventually (3) development of treatments to prevent or reverse the life- threatening consequences of chronic CNS infections. PUBLIC HEALTH RELEVANCE Viral infections of the central nervous system (CNS) are often associated with chronic neurological diseases, rather than the acute illnesses these viruses cause in the periphery. In this application, we focus on measles virus neuropathogenesis using novel mouse models, primary neuronal cell cultures, and human neuronal cell lines. The broad, long-term objectives of this proposal are to define how measles virus particles interact with neuronal proteins to affect both intra- and inter- neuronal viral transport, and to determine how spread across the synapse may contribute to neuropathogenesis. Successful completion of the proposed aims will provide the foundation for the development of treatments to prevent or reverse the life-threatening consequences of chronic CNS infections caused by viruses.

描述（由申请人提供）：许多嗜神经病毒通过突触传播，包括麻疹、脊髓灰质炎、狂犬病和一些疱疹病毒。然而，控制这一过程的病毒蛋白-神经元蛋白相互作用尚不清楚。此外，虽然这些病毒在外周引起快速、高产的感染，但大多数与大脑的慢性感染有关，这可能是由于病毒后代产生和神经元细胞病理学减少所致。因此，该提案的目的是确定病毒（例如麻疹病毒）如何与神经元蛋白质相互作用以影响神经元内和神经元间的运输，并确定这种传播模式如何与慢性中枢神经系统感染相关。这些广泛的目标将通过完成两个具体目标来实现。第一个目标是研究麻疹病毒在神经元内传播到突触，这将表征突触膜上存在的病毒蛋白，以及这些蛋白是否是跨突触传播所必需的。此外，还将确定与控制沿微管运动的细胞运动蛋白的相互作用。第二个目标是解决神经元间麻疹传播问题，并确定一种推定的新型融合蛋白受体神经激肽-1 的作用。具体来说，我们将确定病毒神经传递是否需要神经激肽-1，麻疹融合蛋白和神经激肽-1是否相互作用，以及最终，阻断这种拟议的相互作用如何影响易感转基因小鼠模型中的病毒传播和发病机制。成功完成这些目标将有助于我们的长期目标，包括：（1）识别有助于病毒在神经元中持续存在的细胞因素； (2) 确定病毒持续存在如何导致宿主损伤而不损失神经元；最终 (3) 开发治疗方法来预防或逆转慢性中枢神经系统感染危及生命的后果。公共卫生相关性中枢神经系统 (CNS) 的病毒感染通常与慢性神经系统疾病相关，而不是这些病毒在外周引起的急性疾病。在此应用中，我们使用新型小鼠模型、原代神经元细胞培养物和人类神经元细胞系重点研究麻疹病毒神经发病机制。该提案的广泛、长期目标是确定麻疹病毒颗粒如何与神经元蛋白质相互作用以影响神经元内和神经元间病毒运输，并确定跨突触的传播如何促进神经发病。成功完成拟议目标将为开发预防或逆转病毒引起的慢性中枢神经系统感染危及生命的后果的治疗方法奠定基础。