THE ROLE OF LEUKOCYTE SEQUESTRATION IN THE CONTROL OF VIRALINFECTIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在感染后的一段时间内，许多病毒会导致短暂的I型干扰素依赖型淋巴细胞减少症。哺乳动物宿主采取这种策略的原因一直是人们猜测的主题，但很少有提案能完全令人满意。在我们过去的工作中，我们有了意想不到的发现，一种通常被免疫能力强的小鼠迅速清除的淋巴细胞性脉络膜脑膜炎病毒(LCMV)株会导致严重的淋巴细胞减少症，但建立高水平慢性感染的克隆13株却不会。为了验证克隆13的失败与小鼠清除克隆13的失败相关的假设，我们在感染的急性期用药物FTY720治疗来诱导一过性淋巴细胞减少，FTY720是一种鞘氨醇类似物，通过阻断退出所需的信号将淋巴细胞隔离在淋巴器官中。 最初的结果令人印象深刻：FTY720在感染的第0、1和2天进行了短暂的3天疗程，促进了克隆13的完全清除，包括从通常持续数月的肾脏等器官清除。然后我们得到了一个潜在更重要的结果：在克隆13感染后30天给予FTY720的短暂疗程也诱导了病毒的完全清除。在这两个实验中，清除完全依赖于CD4细胞，这表明该药物不直接作用于病毒。我们最新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.