Structural investigations of the alphaviral lifecycle

描述（由申请人提供）：甲病毒可能是严重的，有时是致命的，属于毒虫科的人类病原体。只有甲病毒和鲁比病毒被归类为托加病毒。甲病毒群在全球广泛分布，除南极洲外，各大洲都已分离出甲病毒属的各种成员。大约有27种不同的甲病毒能够感染各种脊椎动物，如人类、马和啮齿动物。根据它们的分布和它们引起的症状，甲病毒可以进一步分为旧大陆（包括欧洲、亚洲、澳大利亚和非洲）和新世界（包括美洲）。甲病毒在个体和物种之间的传播主要是通过蚊子进行的，这使得甲病毒成为节肢动物传播病毒的成员。疾病可表现为两种一般形式之一，这取决于病毒的类型。旧大陆病毒（即基孔肯雅病毒、罗斯河病毒和辛德比斯病毒）的症状包括发烧、皮疹和关节痛。新世界病毒（即东部、西部和委内瑞拉马脑炎病毒）在高达15%的感染者中表现为发烧、不适、头痛和脑炎，其中儿童的感染率更高。目前，没有有效的疫苗或药物

DESCRIPTION (provided by applicant): Alphaviruses can be serious, sometimes lethal, human pathogens that belong to the family Togaviridae. Only the alphaviruses and the rubiviruses are classified as Togaviruses. The alphavirus group is widely distributed across the globe, and various members of the alphavirus genus have been isolated on every continent except Antarctica. There are approximately 27 different alphaviruses that are capable of infecting various vertebrate species such as humans, horses and rodents. Based on their distribution and the symptoms they cause, the alphaviruses can be further classified as either Old World, which includes Europe, Asia, Australia and Africa or New World, which includes the Americas. Transmission of alphaviruses between individuals and species occurs mostly via mosquitoes, which makes alphaviruses members of the arthropod borne viruses. Disease can be manifested in one of two general forms, which depends on the type of virus. The Old World viruses (i.e. Chikungunya, Ross River and Sindbis viruses) present symptoms including fever, rash and arthralgia. The New World viruses (i.e. eastern, western and Venezuelan equine encephalitis viruses) present with fever, malaise, headache and encephalitis in up to 15% of infections, with a higher rate in children. Currently, there are no effective vaccines or drugs for individuals infected with an alphavirus. Therefore, a better understanding of alphavirus structure and function will aid in the development of safe and effective vaccines. The overall goal of this project is to determine structurally, the steps involved in the alphavirus lifecycle. Symptoms of infection include fever, rash, headache, and sometimes, encephalitis. Today, no effective vaccines exist for alphaviral infections. We will use Venezuelan equine encephalitis virus (VEEV) vaccine strain TC-83 to obtain atomic resolution structures of the virus with associated surface proteins by use of cryo-electron microscopy and x-ray crystallography. By use of neutralizing antibodies, we will trap the virus in intermediate stages of the viral lifecycle, follwed by structural analysis of the virus:antibody complex in order to delineate the complex conformational changes required for viral assembly, infection and maturation. The results of these studies will fill a gap in knowledge surrounding alphavirus assembly, the interaction of the mature virus with neutralizing antibodies, the mechanism by which alphaviruses interact with the lipid membrane of host cells, and provide the knowledge needed for the development of effective drugs and vaccines.