The Role of Leukocyte Sequestration in the Control of Viral Infections

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 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相当多的主题 这些建议都是猜测，但很少有人完全令人满意。最近，我们做了一件意想不到的事 发现一种淋巴细胞性脉络丛脑膜炎病毒（LCMV）株，通常通过 免疫活性小鼠的Armstrong株诱导了严重的淋巴细胞减少，但克隆13株， 而不是高水平的慢性感染。为了验证这一假设， 克隆13诱导淋巴细胞减少症与小鼠清除克隆13的失败有关，我们诱导了短暂的 在感染的急性期通过药物FTY 720治疗的淋巴细胞减少，FTY 720是一种鞘氨醇类似物， 通过阻断淋巴细胞离开所需的信号将淋巴细胞隔离在淋巴器官中。结果 休克：在感染的第0、1和2天，FTY 720的短暂的三天疗程促进了完全 清除克隆13，包括从肾脏等器官中清除，而病毒通常会在肾脏中持续数月。 然后，我们获得了一个可能更重要的结果：在30 ℃下，FTY 720的短暂过程 克隆13感染后30天也诱导病毒的完全清除。在两个实验中，清除率均为 完全依赖于CD4细胞，表明药物不直接作用于病毒。这些 这些发现提出了一些重要的问题，我们将在本基金中解决这些问题。在目标1中，我们将探索 FTY720促进LCMV清除的机制。在目标2中，我们会问， FTY720还诱导逆转LCMV诱导的全身免疫抑制。最后，在目标3中，我们将问 FTY720是否也能改善对其他病毒感染的免疫反应。在这些实验中，我们将 四个良好建立的病毒感染小鼠模型：用牛痘病毒致死的鼻内感染，致死的 流感病毒鼻内感染，多瘤病毒感染新生肿瘤易感小鼠， γ疱疹病毒68潜伏感染建立。FTY 720治疗，作用于免疫球蛋白 细胞，没有直接的特异性抗病毒作用，可能被证明可用于治疗慢性病毒感染， 人类，如HIV、HBV或HCV。

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.