The 'Spanish' influenza pandemic of 1918-19 was the largest outbreak of any infectiousdisease in recorded history, killing approximately 20-40 million people worldwide. Directstudy of this virus has been impossible because the pandemic pre-dated the first successfulidentification and isolation of the causative agent. However, recent gene assembly of viralRNA fragments has facilitated insights into the virus composition. The main goal of thisproposal is to study the protein antigens from these assembled genes to understand, from astructural viewpoint, why this virus was so virulent. Protein components of the virus will becloned, expressed and purified in sufficient quantities to crystallize and determine their X-raystructures. Initially, the main thrust of this project will be to study the two major antigenicepitopes, hemagglutinin (HA) and neuraminidase (NA). The structures of both proteins willbe determined alone and in complex with relevant ligands. For the hemagglutinin, both theprecursor (HA0) and cleaved protein (HAl/HA2) will be investigated. Fragments of the HAwill be produced to elucidate the acid-induced conformational changes which occur duringvirus entry and membrane fusion. In addition, complexes with neutralizing antibodies willinvestigate the structural basis of viral neutralization. For the neuraminidase, complexeswith substrate and current antiviral drugs, effective against influenza viruses will aid infuture design of anti-virals specific for the Spanish flu. Finally, a third 1918 influenza protein,the multifunctional nonstructural protein (NS1) will be investigated. These structural resultscan be combined with data from the other projects to explain the severity of this virus andwhat steps can be taken to counter future outbreaks, originating from either natural or bio-terrorist sources.
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