Immunoregulation of Flavivirus Infection

描述(由申请人提供)：西尼罗河病毒感染可在生殖性感染后造成严重的衰弱后果。可能会导致严重的脑炎，可能会导致神经功能障碍和死亡。目前还没有疫苗可用，只有在临床发现感染证据后才能进行针对症状的治疗。对病毒感染的免疫反应最初包括先天反应，随后是适应性反应。这种先天反应既可以调节病毒的清除，也可以调节病毒的发病。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，从而增强它们的传染性。由于所使用的佐剂，接种疫苗后也会诱发先天反应，因此，了解这些反应将有助于制定适当的疫苗接种策略。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应用中，我们试图定义宿主对西尼罗河病毒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，我们需要支持才能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马戈·布林顿博士之间的战略合作，布林顿博士是西尼罗河病毒领域的知名研究员。这种合作对于我们在这些西尼罗河病毒研究中取得成功至关重要。我们建议在这个修订的探索性R21应用中检验两个假设。首先，我们将检验一种假设，即在感染西尼罗河病毒后，NK谱系既被激活又被改变。其次，我们将验证NK反应是病毒清除所必需的假设，但也参与病毒的致病过程。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.