Immunoregulation of Flavivirus Infection

描述（由申请人提供）：西尼罗河病毒感染可导致生产性感染后严重衰弱的后果。 严重的脑炎可能导致神经功能障碍和死亡。没有可用的疫苗，只有在感染的临床证据之后才有针对性的治疗。对病毒感染的免疫应答最初涉及先天应答，随后是适应性应答。先天性应答可以调节病毒清除以及病毒的发病机制。 事实上，一些病毒已经发展出复杂的能力来调节先天免疫反应，从而增强其传染性。由于使用的佐剂，在接种后也诱导先天性应答，因此，对这些应答的理解将允许开发适当的接种策略。几乎没有关于西尼罗河病毒先天免疫反应的报道。因此，在这个修订的探索性R21应用程序中，我们试图定义宿主对西尼罗河病毒的先天反应的关键方面。我们选择R21机制有几个原因。首先，由于对西尼罗河病毒的先天反应知之甚少，我们需要对感染后激活的细胞和受体进行探索性研究。其次，这种黄病毒的使用在我们的实验室是新的，我们需要支持，以便能够在我们的实验室内启动对这种重要病毒的研究。重要的是，我们已经安排了我们的实验室和西尼罗河病毒领域的知名研究人员Margo Brinton博士之间的战略合作。这种合作对于我们在这些西尼罗河病毒调查中取得成功至关重要。我们建议在这个修订后的探索性R21应用程序中测试两个假设。首先，我们将测试的假设，即NK细胞库被激活和改变后感染西尼罗河病毒。其次，我们将检验NK应答是病毒清除所必需的，但也参与病毒发病机制的假设。 我们相信，从我们的研究中获得的信息将突出NK细胞及其受体在宿主对西尼罗河病毒的反应中的作用。

DESCRIPTION (provided by applicant): West Nile virus infection can cause severe debilitating consequences following productive infection. Severe encephalitis can result, which can lead to neurological dysfunction and death. There is no vaccine available, and only symptom-specific treatment following clinical evidence of infection. Immune responses to viral infections involve innate responses initially, which are followed by adaptive responses later. The innate response can modulate both viral clearance as well as pathogenesis of the virus. Indeed some viruses have developed sophisticated abilities to modulate the innate immune response, enhancing their infectivity. Innate responses are also induced following vaccination, due to the adjuvants utilized, and therefore, an understanding of these responses will allow for the development of appropriate vaccination strategies. There are virtually no reports available characterizing the innate immune response to West Nile virus. Therefore, in this revised exploratory R21 application we seek to define critical aspects of the host innate response to West Nile virus. We have chosen the R21 mechanism for several reasons. First, since little is known about the innate response to West Nile Virus, we will need to perform exploratory studies regarding the cell and receptors activated following infection. Secondly, the use of this flavivirus is new in our laboratory and we require support to be able to initiate studies on this important virus within our laboratory. Importantly we have arranged for a strategic collaboration between our laboratory and Dr. Margo Brinton, an established investigator in the West Nile virus field. This collaboration will be critical for our success in these West Nile virus investigations. We propose to test two hypotheses in this revised exploratory R21 application. Firstly, we will test the hypothesis that the NK repertoire is both activated and altered following infection by West Nile virus. Secondly, we will test the hypothesis that NK responses are required for viral clearance, but are also involved in viral pathogenesis. We believe that the information obtained from our studies will highlight the role of NK cells and their receptors in the host response to West Nile virus.