Cytomegalovirus in the Brain

大脑中的巨细胞病毒

• 批准号: 7172987
• 负责人: ANTHONY N VAN DEN POL
• 金额: $ 40.05万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172987
• 关键词: Acquired Immunodeficiency Syndrome; Activated Lymphocyte; Acute; Address; Area; Axon; Axonal Transport; Binding; Brain; Brain Diseases; Brain region; Calcium; Cell membrane; Cells; Characteristics; Child; Clinical; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Development; Disease; Electron Microscopy; Epilepsy; Functional disorder; Fura-2; Gene Expression; Genes; Genome; Green Fluorescent Proteins; Harvest; Image; Immunocompromised Host; In Vitro; Infection; Interferon Receptor; Interferon-alpha; Interferons; Ions; Lead; Link; Lymphocyte; Mediating; Membrane; Mental Retardation; Microcephaly; Microgyria; Microscopy; Modeling; Motor; Murid herpesvirus 1; Mus; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurons; Pathway interactions; Patients; Peripheral; Physiological; Plaque Assay; Portal System; Property; Recombinants; Recovery; Reporter Genes; Resistance; SCID Mice; Sensory; Series; Slice; Surface; System; Testing; Toxic effect; Viral; Virus; Virus Diseases; Whole-Cell Recordings; Work; base; brain cell; deafness; digital; digital imaging; in vivo; nervous system disorder; patch clamp; preference; receptor; research study; response; voltage clamp

DESCRIPTION (provided by applicant): Within the brain, cytomegalovirus (CMV) is the leading viral cause of congenital disease, often producing serious neurological deficits. By attacking the developing CNS, CMV causes serious brain disorders that include microencephaly, epilepsy, deafness, microgyria, mental retardation, sensory loss, motor problems, and psychiatric disturbances. CMV is also a clinically important opportunistic virus that can lead to serious neurological disease in AIDS patients. Despite the clinical importance of CMV infections of the brain, relatively little experimental work has been done in this area, and many basic questions remained unanswered. The present application addresses basic mechanisms of viral spread into and within the brain, and the repercussions of this infection. A recombinant mouse CMV expressing GFP will be used to identify infected cells and track virus dispersal. CMV shows rapid dispersal in developing but not mature brain; the hypothesis that CMV can be spread through axonal transport, but only in the developing axon, will be tested. The hypothesis that interferons alpha/beta and gamma can reduce or eliminate CMV from the brain will be addressed with in vitro and in vivo experiments. Parallel experiments will test the hypothesis that CMV activates interferon pathways in the mature brain, but not in the developing brain. Mice lacking interferon receptors will be used to test further that CMV effects are mediated by these receptors and not by a non-specific action of CMV. An ultrastructural analysis will assess differential virus binding to immature and mature neurons, and determine where on the neuron surface CMV binds. In the immunocompromised CNS, the olfactory system shows the greatest levels of infection; we will address the hypothesis that the olfactory system is a weak link in the brain's protection against virus in SCID mice. The hypothesis that neurons that recover from CMV still show physiological dysfunction will be tested with whole cell patch clamp recording using current and voltage clamp and with fura-2 calcium digital imaging. CMV can remain latent for long periods. We will test the hypothesis that after interferon or gangciclovir treatment and recovery from infection, CMV can escape from neuronal latency, and establish a new round of productive infectious virus. These experiments will help us understand the mechanisms associated with CMV-induced neurological dysfunction, and how to combat the virus within the brain with minimal complications.

描述（由申请人提供）：在大脑内，巨细胞病毒（CMV）是先天性疾病的主要病毒原因，通常会导致严重的神经缺陷。通过攻击开发的CNS，CMV会引起严重的脑部疾病，包括微脑，癫痫，耳聋，微毛，智力低下，智力低下，感觉丧失，运动问题和精神病患者。 CMV也是一种临床上重要的机会病毒，可以导致艾滋病患者严重的神经疾病。尽管大脑CMV感染的临床重要性，但在这一领域进行了相对较少的实验性工作，许多基本问题仍然没有解决。目前的应用程序解决了病毒扩散到大脑内外的基本机制，以及这种感染的影响。表达GFP的重组小鼠CMV将用于鉴定受感染的细胞并跟踪病毒分散。 CMV显示出在发展但不成熟的大脑中的快速扩散。 CMV可以通过轴突运输而扩散但仅在发育中的轴突中进行测试的假设。干扰素α/β和伽马可以通过体外和体内实验来解决或消除大脑中的CMV的假设。平行实验将检验以下假设：CMV激活成熟大脑中的干扰素途径，但不会在发育中的大脑中激活干扰素。缺乏干扰素受体的小鼠将进一步测试CMV效应是由这些受体介导的，而不是通过CMV的非特异性作用介导的。超微结构分析将评估与未成熟和成熟神经元结合的鉴别病毒，并确定神经元表面CMV的位置结合。在免疫功能低下的中枢神经系统中，嗅觉系统显示出最大的感染水平。我们将解决以下假设：嗅觉系统是大脑对SCID小鼠病毒的保护的薄弱环节。从CMV中恢复的神经元仍显示生理功能障碍的假说将使用电流和电压夹以及Fura-2钙数字成像进行测试。 CMV可以长期保持潜在。我们将检验以下假设：干扰素或黑帮治疗并从感染中恢复后，CMV可以逃脱神经元潜伏期，并建立新的一轮生产性传染病。这些实验将有助于我们了解与CMV诱导的神经功能障碍相关的机制，以及如何以最小的并发症来对抗大脑中的病毒。