The Role of Leukocyte Sequestration in the Control of Viral Infections

白细胞隔离在控制病毒感染中的作用

基本信息

批准号：
7826196
负责人：
John David Altman
金额：
$ 43.37万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-03 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7826196
关键词：
Acute Address Adopted Adoptive Transfer Agonist Animals Antigens Antiviral Agents Antiviral Response Binding Biological Assay Bone Marrow Busulfan CD4 Positive T Lymphocytes CD8B1 gene Cells Chimera organism Chronic Collection Control Animal Critiques Development Down-Regulation FK506 Failure Frequencies Goals Grant HIV Hepatitis B Virus Hepatitis C virus Human Immune response Immune system Immunity Immunocompetent Immunosuppression Infection Interferon Type I Kidney Lead Leukocytes Lymphocyte Lymphocytic choriomeningitis virus Lymphoid Lymphopenia Memory Modeling Mus Newborn Infant Organ Pharmaceutical Preparations Phase Polyomavirus Recruitment Activity Role Series Signal Transduction Source Sphingosine Sphingosine-1-Phosphate Receptor T-Cell Activation T-Lymphocyte Testing Time Transgenic Organisms Treatment Protocols Vaccinia Vaccinia virus Viral Virus Virus Diseases Wild Type Mouse analog conditioning exhaust expectation experience gammaherpesvirus improved influenzavirus latent infection lymph nodes mouse model prevent research study response trafficking tumor

项目摘要

In the period immediately following infection, many viruses cause a transient, type I interferon-dependent lymphopenia. The reason that mammalian hosts adopt such a strategy has been the subject of considerable speculation, but few of the proposals have been completely satisfactory. Recently, we made the unexpected discovery that a strain of lymphocytic choriomeningitis virus (LCMV) that is normally rapidly cleared by immmunocompetent mice¿the Armstrong strain¿induces a profound lymphopenia, but the clone 13 strain, which establishes a high level chronic infection, does not. In order to test the hypothesis that the failure of clone 13 to induce lymphopenia was associated with the failure of mice to clear clone 13, we induced transient lymphopenia during the acute phase of infection by treatment with the drug FTY720, a sphingosine analog that sequesters lymphocytes in lymphoid organs by blocking signals required for their exit. The results were stunning: a transient, three day course of FTY720 at days 0, 1, and 2 of the infection promoted complete clearance of clone 13, including from organs such as the kidneys where the virus normally persists for months. We then obtained a result that is potentially even more important: a transient course of FTY720 given at 30 days post clone 13 infection also induced complete clearance of the virus. In both experiments, clearance was completely dependent upon CD4 cells, demonstrating that the drug is not acting directly on the virus. These discoveries raise a number of important questions that we will address in this grant. In Aim 1, we will explore the mechanisms through which FTY720 is promoting clearance of LCMV. In Aim 2, we will ask whether FTY720 also induces reversal of LCMV-induced generalized immunosuppression. Finally, in Aim 3, we will ask whether FTY720 also improves immune responses to other viral infections. For these experiments we will turn to four well established mouse models of viral infection: lethal intranasal infection with vaccinia virus, lethal intranasal infection with influenza virus, infection of newborn tumor-susceptible mice with polyoma virus, and establishment of latent infection with gammaherpesvirus 68. Treatment with FTY720, which acts on hostimmune cells and has no direct specific antiviral effects, might prove useful in treating chronic viral infections in humans, such as HIV, HBV, or HCV.

在感染后的一段时间内，许多病毒会引起短暂的、I 型干扰素依赖性的哺乳动物宿主采取这种策略的原因一直是相当多的话题。猜测，但很少有建议是完全令人满意的。最近，我们提出了意想不到的建议。发现一种淋巴细胞性脉络丛脑膜炎病毒（LCMV）通常可被快速清除免疫能力强的小鼠??阿姆斯特朗菌株¿引起严重的淋巴细胞减少症，但克隆 13 菌株，这建立了高水平的慢性感染，但并没有检验失败的假设。克隆13诱导淋巴细胞减少症与小鼠未能清除克隆13有关，我们诱导了短暂的通过药物 FTY720（一种鞘氨醇类似物）治疗，感染急性期出现淋巴细胞减少症通过阻断淋巴细胞排出所需的信号将淋巴细胞隔离在淋巴器官中。击晕：在感染第 0、1 和 2 天使用 FTY720 进行短暂的三天疗程，促进完全清除克隆 13，包括从肾脏等器官中清除，病毒通常在这些器官中持续数月。然后我们获得了一个可能更重要的结果：FTY720 在 30 时的瞬态过程克隆 13 感染后几天也诱导了病毒的完全清除。完全依赖于 CD4 细胞，表明该药物不直接作用于病毒。这些发现提出了许多重要问题，我们将在目标 1 中探讨这些问题。 FTY720 促进 LCMV 清除的机制在目标 2 中，我们将询问是否。 FTY720 还可以逆转 LCMV 诱导的全身免疫抑制。最后，在目标 3 中，我们会问。 FTY720 是否也能改善对其他病毒感染的免疫反应？四种已建立的病毒感染小鼠模型：致死性牛痘病毒鼻内感染、致死性鼻内感染流感病毒、新生肿瘤易感小鼠多瘤病毒感染，以及建立伽马疱疹病毒 68 潜伏感染。用 FTY720 治疗，作用于宿主免疫细胞并且没有直接的特异性抗病毒作用，可能有助于治疗慢性病毒感染人类，例如 HIV、HBV 或 HCV。