Structural investigations of the alphaviral lifecycle

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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.