THE ROLE OF LEUKOCYTE SEQUESTRATION IN THE CONTROL OF VIRALINFECTIONS

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在感染后不久，许多病毒会引起短暂的 I 型干扰素依赖性淋巴细胞减少症。哺乳动物宿主采取这种策略的原因引起了相当多的猜测，但很少有人提出完全令人满意的建议。在我们过去的工作中，我们意外地发现，淋巴细胞性脉络膜脑膜炎病毒（LCMV）病毒株（阿姆斯特朗株）通常会被免疫功能正常的小鼠迅速清除，但它会引起严重的淋巴细胞减少症，但克隆13株则不会引起高度慢性感染。为了检验克隆 13 未能诱导淋巴细胞减少与小鼠未能清除克隆 13 相关的假设，我们通过药物 FTY720 治疗在感染急性期诱导短暂的淋巴细胞减少，FTY720 是一种鞘氨醇类似物，通过阻断退出所需的信号来隔离淋巴器官中的淋巴细胞。 初步结果令人印象深刻：在感染的第 0 天、第 1 天和第 2 天，FTY720 短暂的三天疗程促进了克隆 13 的完全清除，包括从肾脏等器官中彻底清除，而病毒通常会在这些器官中持续数月。然后我们获得了一个可能更为重要的结果：在克隆 13 感染后 30 天给予 FTY720 短暂疗程也诱导了病毒的完全清除。在这两个实验中，清除率完全依赖于 CD4 细胞，这表明该药物并不直接作用于病毒。我们最近的工作试图验证这些结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 proposals have been completely satisfactory. In our past work, we made the unexpected discovery that a strain of lymphocytic choriomeningitis virus (LCMV) that is normally rapidly cleared by immmunocompetent micethe Armstrong straininduces a profound lymphopenia, but the clone 13 strain, which establishes a high level chronic infection, does not. In order to test the hypothesis that failure of clone 13 to induce lymphopenia was associated with failure of mice to clear clone 13, we induced transient lymphopenia during the acute phase of infection by treatment with drug FTY720, a sphingosine analog that sequesters lymphocytes in lymphoid organs by blocking signals required for exit. The initial results were impressive: a transient, three day course of FTY720 at days 0, 1, and 2 of infection promoted complete clearance of clone 13, including from organs such as kidneys where 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 virus. In both experiments, clearance was completely dependent upon CD4 cells, demonstrating that the drug is not acting directly on virus. Our most recent work has sought to validate these results.