Immunopathogenesis of West Nile virus encephalitis - requirement for interferon-gamma-dependent soluble mediators

节肢动物传播的黄病毒有引起脑炎的倾向，在世界范围内会导致相当大的疾病和死亡。1999年8月，西尼罗河病毒(WNV)脑炎首次在纽约爆发，表明这些病毒正在蔓延到流行地区以外。然而，这些病毒致死人的机制还完全不清楚。免疫系统如何处理它们是由一个复杂的相互作用网络控制的，这个网络涉及细胞和可溶性介质，如细胞因子、趋化因子和一氧化氮，其中许多是由细胞因子干扰素-γ诱导或调节的。有证据表明，这些药物共同影响被动员起来根除病毒的细胞类型，也影响疾病结果。我们的假设是，宿主自身的免疫系统通过过度积极地试图摧毁感染病毒，从而对大脑造成损害，从而无意中导致脑炎。为了研究西尼罗河病毒脑炎，我们使用了本实验室开发的复制人类疾病特征的小鼠模型。另一种小鼠的干扰素基因失活或被“敲除”，因此它们不能以常规方式对病毒感染做出反应。这只小鼠在西尼罗河病毒感染中的存活率明显高于正常小鼠，并具有免疫力。因此，我们将比较这些小鼠在WNV感染期间的细胞和可溶性介质反应与正常小鼠的反应。我们还将删除正常小鼠中产生干扰素-γ的特定细胞类型，并将这些细胞转移到基因敲除小鼠中。实验将指出哪种细胞类型是罪魁祸首，以及特定成分何时造成最大损害。因此，在这个模型中，我们将更好地理解干扰素-伽马是如何招募介导免疫脑损伤的细胞的。通过了解导致脑炎死亡的事件，有可能通过免疫干预的方式预防或改善这些事件。

Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble mediators such as cytokines, chemokines, and nitric oxide, many induced or modulated by the cytokine, inteferon-gamma. Evidence suggests that these agents together influence both the types of cells that are mobilised to eradicate virus and also disease outcomes. Our hypothesis is that the host's own immune system is inadvertently responsible for encephalitis through an over-vigorous attempt to destroy the infecting virus, resulting in damage to the brain. To study WNV encephalitis, we are using a mouse model developed in this laboratory that reproduces the features of human disease. Another strain of these mice has the gene for interferon-gamma (IFN) inactivated or 'knocked out', so they cannot respond in the conventional way to virus infection. This mouse survives WNV infection significantly better than normal mice and becomes immune. Therefore we will compare cellular and soluble mediator responses of these mice during WNV infection to those of normal mice. We will also delete specific cell types making interferon-gamma in normal mice, as well as transfering such cells into knockout mice. Experiments will indicate which cell types are responsible and when particular components cause most damage. Thus, we will better understand how interferon-gamma recruits cells that mediate immune brain damage in this model. By understanding the events that lead to death in encephalitis, it may be possible to prevent or ameliorate them by means of immune intervention.