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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：进行性多灶性白质脑病 (PML) 是一种潜在致命的中枢神经系统 (CNS) 脱髓鞘疾病，由潜伏 JC 多瘤病毒 (JCPyV) 重新激活引起，JCPyV 是一种高度嗜神经性的人类多瘤病毒，通过溶解性感染引发疾病大约 50-70% 的普通人群曾接触过少突胶质细胞。 JCPyV；感染通常在临床上不明显，PML 可能发生在器官移植或化疗后的免疫抑制/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 通常会出现明显的免疫抑制。然而，最近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发的 PML 的存在，导致 PML 的免疫调节疗法的例子包括：那他珠单抗（Tysabri(r)），一种针对整合素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CD20的嵌合单克隆抗体，用于治疗类风湿性关节炎）；一种针对整合素 aLβ2 的人源化中和单克隆抗体，用于治疗牛皮癣。表明多瘤病毒重新激活导致的 PML 的发展应该是开发针对自身免疫性疾病的新型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，是一个独立的物种。其他研究表明，断奶小鼠的感染会导致不明显的临床疾病，但其组织分布却不同。 MPtV 的感染情况与在感染人类多瘤病毒的人类中观察到的情况类似，大约六个月后，在任何组织中都检测不到传染性 MPtV。然而，每周向潜伏感染的小鼠注射环磷酰胺（一种免疫抑制剂），结果在各种组织中都检测到了病毒。环磷酰胺治疗后一周，病毒数量增加，直到免疫抑制治疗后第 14 天，通过免疫荧光染色和病毒分离，在体内检测到病毒。肺、肝、脾、肾、肠和中枢神经系统中的血管内皮细胞中以及免疫抑制后的肾小管上皮细胞中都发现了病毒。这与人多瘤病毒 JCPyV 相似，其中病毒重新激活导致检测到。体外研究表明，MPtV 也可以在小鼠神经胶质细胞中持续存在，这表明我们建议开发一种可能的病毒潜伏位点。我们将探索该模型是否可以作为一种可行且潜在有用的试剂来测试中枢神经系统中多瘤病毒重新激活的问题。免疫调节疗法如何导致中枢神经系统中的人类多瘤病毒重新激活。