Mouse Pneumotropic Virus Infection: A Model for JC Virus Latency and Reactivation

小鼠嗜肺病毒感染：JC 病毒潜伏期和再激活模型

• 批准号: 8874456
• 负责人: Robert S Fujinami
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874456
• 关键词: Acquired Immunodeficiency Syndrome; Antibody Response; Astrocytes; Autoimmune Diseases; Biological Assay; Bone Marrow; Brain; Clinical; Colon; Crohn' s disease; Cyclophosphamide; Development; Disease; Drug or chemical Tissue Distribution; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Experimental Animal Model; General Population; Human; Immunocompromised Host; Immunofluorescence Immunologic; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; In Situ Hybridization; In Vitro; Incidence; Individual; Infection; Injection of therapeutic agent; Integrins; Intestines; JC Virus; Kidney; Kinetics; Latent Virus; Lead; Liver; Location; Lung; MS4A1 gene; Marketing; Microglia; Modeling; Monoclonal Antibodies; Mus; Neuraxis; Neuroglia; Neurons; Oligodendroglia; Organ; Organ Transplantation; Patients; Polyomavirus; Polyomavirus Infections; Progressive Multifocal Leukoencephalopathy; Psoriasis; Reagent; Relapsing-Remitting Multiple Sclerosis; Reporting; Rheumatoid Arthritis; Serum; Site; Spleen; Staining method; Stains; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Transgenic Mice; Tubular formation; Tysabri; Vascular Endothelial Cell; Viral Genome; Virus; Virus Diseases; Virus Latency; central nervous system demyelinating disorder; chemotherapy; efalizumab; humanized monoclonal antibodies; immunosuppressed; latent infection; lymph nodes; member; mouse polyomavirus; natalizumab; neurotropic; neutralizing monoclonal antibodies; new technology; novel; public health relevance; receptor; rituximab; viral detection

 DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of latent JC polyomavirus (JCPyV), a highly neurotropic human polyomavirus, which initiates disease by lytically infecting oligodendrocytes. Approximately 50-70% of the general population has been exposed to JCPyV; the infection is usually clinically inapparent and the virus remains latent. PML can occur in immunosuppressed/immunocompromised individuals following organ transplantation or chemotherapy as well as in about 3-5% of acquired immunodeficiency syndrome cases. Therefore, PML usually follows marked immunosuppression. However, the recent development of immunomodulatory therapies for the treatment of various autoimmune diseases has led to the existence of therapy-induced PML. Examples of immunomodulatory therapies resulting in PML include: natalizumab (Tysabri(r)), a humanized monoclonal antibody (mAb) against the integrin α4β1 for the treatment of relapsing- remitting multiple sclerosis and Crohn's disease; rituximab, a chimeric mAb against CD20, for the treatment of rheumatoid arthritis; and efalizumab, a humanized neutralizing mAb against the integrin aLβ2 for the treatment of psoriasis. This demonstrates that the development of PML due to polyomavirus reactivation should be a major concern in the development of new immunomodulatory therapeutics for autoimmune diseases. Murine pneumotropic virus (MPtV), formerly known as Kilham polyomavirus, is a member of the Polyomavirus genus that infects mice. This virus is distinct from mouse polyomavirus (MPyV) and is a separate species. Others have shown that infection of weanling mice leads to inapparent clinical disease; however, the tissue distribution of MPtV is similar to what is observed in humans infected with human polyomavirus. After about six months, infectious MPtV was not detectable in any tissues. However, weekly injections of cyclophosphamide, an immunosuppressive agent, into latently infected mice resulted in detectable virus in various organs as soon as one week post-cyclophosphamide treatment. Virus increased in amount until day 14 post-immunosuppressive treatment. By immunofluorescence staining and virus isolation, virus was detected in lung, liver, spleen, kidney, intestine and CNS. Virus has been found in vascular endothelial cells in the CNS and, following immunosuppression, in renal tubular epithelial cells. This is similar to the human polyomavirus JCPyV where virus reactivation results in the detection of virus in tubular epithelium. In vitro studies have shown that MPtV can also persist in murine glial cells, suggesting a possible site of viral latency. We propose to develop a novel viral latency model using MPtV infection of mice. We will explore whether this model can be a viable and potentially useful reagent to test immunomodulatory therapies where polyomavirus reactivation in the CNS is a problem. Currently there is no good model that can be used to predict how immunomodulatory therapies lead to human polyomavirus reactivation in the CNS.

 描述（由申请方提供）：进行性多灶性白质脑病（PML）是一种潜在致死性中枢神经系统（CNS）脱髓鞘疾病，由潜伏JC多瘤病毒（JCPyV）再活化引起，JCPyV是一种高度嗜神经的人多瘤病毒，通过溶解性感染少突胶质细胞引发疾病。大约50-70%的普通人群暴露于JCPyV;感染通常在临床上不明显，病毒保持潜伏状态。PML可发生在器官移植或化疗后免疫抑制/免疫功能低下的个体中，以及约3-5%的获得性免疫缺陷综合征病例中。因此，PML通常伴随明显的免疫抑制。然而，近年来用于治疗各种自身免疫性疾病的免疫调节疗法的发展导致了治疗诱导的PML的存在。导致PML的免疫调节疗法的实例包括：那他珠单抗（Tysabri（r）），一种针对整联蛋白α4β1的人源化单克隆抗体（mAb），用于治疗复发缓解型多发性硬化症和克罗恩病;利妥昔单抗，一种针对CD 20的嵌合mAb，用于治疗类风湿性关节炎;和依法珠单抗，一种针对整联蛋白α L β2的人源化中和mAb，用于治疗银屑病。这表明，由于多瘤病毒再活化导致的PML的发展应该是开发用于自身免疫性疾病的新免疫调节疗法的主要关注点。 鼠嗜肺病毒（MPTV），以前称为Kilham多瘤病毒，是感染小鼠的多瘤病毒属的成员。这种病毒与小鼠多瘤病毒（MPyV）不同，是一个单独的物种。其他人已经表明，断奶小鼠的感染导致不明显的临床疾病;然而，MPtV的组织分布与感染人多瘤病毒的人中观察到的相似。大约六个月后，在任何组织中都检测不到感染性MptV。然而，每周注射环磷酰胺，一种免疫抑制剂，进入潜伏感染的小鼠导致检测到病毒在各种器官尽快环磷酰胺治疗后一周。直到免疫抑制治疗后第14天，病毒量增加。通过免疫荧光染色和病毒分离，在肺、肝、脾、肾、肠和中枢神经系统中检测到病毒。在CNS的血管内皮细胞中发现了病毒，在免疫抑制后，在肾小管上皮细胞中也发现了病毒。这类似于人多瘤病毒JCPyV，其中病毒再活化导致在肾小管上皮中检测到病毒。体外研究表明，MPtV也可以在鼠神经胶质细胞中持续存在，表明病毒潜伏期的可能位点。 我们建议开发一种新的病毒潜伏期模型，使用MPTV感染的小鼠。我们将探讨这种模型是否可以成为一种可行的和潜在有用的试剂，以测试免疫调节疗法，其中多瘤病毒在中枢神经系统中的再活化是一个问题。目前还没有一个很好的模型可以用来预测免疫调节治疗如何导致人多瘤病毒在中枢神经系统中的再活化。