The Ebola virus causes a severe hemorrhagic fever for which no approved vaccines or treatments are yet available. Two viral glycoproteins play an important role in Ebola viral pathogenesis. These two proteins, sGP and GP, share an identical 295 amino acid sequence at their N termini, but have different C termini that lead to different patterns of disulfide bonding and different tertiary structures. Importantly, the different structures lead to unique roles in pathogenesis for the two proteins. GP exists as a trimer on the viral surface and mediates cell attachment and fusion. In contrast, sGP is a dimer and is secreted abundantly from infected cells. In natural infection, the majority of antibodies are bound by the secreted sGP and not the virion surface GP. Understanding how to elicit antibodies specific for GP will be critical for the design of vaccines and immunotherapeutics for long-term and immediate immunity in case of natural outbreak or deliberate release of Ebola virus. X-ray crystallography is the best way to clearly map structural differences between sGP and GP. These structures will also provide the templates by which we may understand the roles of these proteins in the viral life cycle.
Our specific aims are to determine X-ray crystal structures of sGP and GP and to characterize antibodies directed against them. Our objectives are to (1) determine why it is difficult to elicit neutralizing antibodies against GP in natural infection, (2) identify structural elements unique to GP that can be exploited for design of vaccines and immunotherapeutics, (3) map ligand and receptor binding sites on the glycoproteins and importantly, (4) map key differences in GP sequence from Ebola viral subtypes that are pathogenic and nonpathogenic to humans. Our extensive preliminary data demonstrate the feasibility of these specific aims.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067927-07
Application #
8289517
Study Section
Virology - A Study Section (VIRA)
Program Officer
Repik, Patricia M
Project Start
2006-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$443,226
Indirect Cost
$209,827
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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