Influenza is a serious disease. Annual epidemics have a major impact on health and economy worldwide, and influenza continues to elude the vaccines which are painstakingly redesigned every year in response to antigenic variation of the circulating viruses. In the United States, 10,000 - 20,000 influenza-associated deaths occur in an average winter, primary among children, elderly persons and those with risk factors such as respiratory disease, or immune suppression due to chemotherapy of cancer or AIDS. Estimated costs to the economy of the U.S.A. are $1 billion to $3 billion each winter. Influenza viruses initiate infection by attaching to sialic acid receptors on cell surfaces by the hemagglutinin (HA) viral glycoprotein. The virus also has a receptor-destroying enzyme, neuramindase (NA), on its surface. The NA is necessary for virus release and spread after each replication cycle. The long term goals of this proposal are to determine if inhibitors of NA will be useful antiviral agents, effective against type A and type B influenza. One question to be addressed ins why viruses that recognize sialic acid (influenza, some paramyxoviruses, some coronaviruses) need a receptor-destroying enzyme when most viruses have no such activity. One hypothesis is that a virus requires a receptor- destroying activity only if that receptor can be incorporated into the virion structure. If the sole function of NA is to prevent HA-HA aggregation, a virus could become resistant to NA inhibitors by altering its receptor specificity or by eliminating from its HA the complex carbohydrates that bear sialic acid. It seems likely that the NA has a more complex role in the infected person, particularly given the importance of sialic acids in regulation of the immune system. The objectives for this granting period ar to investigate the specificity of attachment by the HA and of release by the NA, to understand more fully the role of NA in infection and pathogenesis.
The Specific Aims are:
Aim 1 : To determine the variety of sialic acid structures recognized by influenza viruses, and to investigate if other molecules are involved in recognition and entry into cells.
Aim 2 : To determine the role(s) of NA activity in influenza infection.
Aim 3 : To investigate if the NA activity in a paramyxovirus, where it is on the same molecule as the receptor-binding activity, has the same functions as for influenza virus. The biochemical and biological experiments proposed will provide essential data to guide subsequent investigation into the disease and its control, particularly to evaluate the potential for resistance if the NA is the target of antivirals designed against influenza and parainfluenza.
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