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This project extends our published ebola (EBOV) gp's structures, and furthers our studies for immune targeting. Taking a holistic approach our studies aim to examine both the standard seasonal immunity approach to build strong immune responses to specific strains (and their close relatives) as well as a broader strain-independent approach that we (GWL and JSS) have identified as a 2nd pathway of adaptive immunity, for delivery of seasoned immunity©, for Vaccines that could target all strains of Ebola and perhaps also other filoviruses, such as Marburg.
Camperdown - Central Clinical School
Masters/PHD
Background: Quite astoundingly sections of the protein structure of the envelope glycoprotein gp on the surface of the Ebola virus, a principal effector for cell infection as well as target for immune control and vaccines, remains to be fully clarified. At the apex of gp is a mucin-like-domain, that because of its flexible structure has resisted definition by crystallography. Using computational and immunological studies we have already revealed structures, glycosylations and immune sites for Ebola's gp glycoprotein for both strain-specific targeting and broader strain-independent targeting, which without a structure, was till then largely unidentified or unmapped.
Approach: Using computational, proteomic and laboratory based determinations, to determine the structures and most vulnerable sites of the envelope glycoproteins of Ebola and Marburg. Test these in in silico and in vitro-based assays, experiments will be performed to further characterize the Antibody specificities both between Ebola strains and for the respective gp proteins, as well as its soluble forms. These studies when performed in parallel peptide and recombinant protein analysis to provide characterization of the anti-Ebola activities of IVIGs and Human sera. These studies will also focus on the mucin-like domains, as structural similarities with the mucin proteins of host mucosal surfaces.
Significance: In the event of further outbreaks of Ebola or another filovirus such as Marburg, needed is a clear understanding of what if any Antibody immunity might exist ahead of the next outbreak. This is necessary to define those in the population at greatest risk, and those who are the best candidates for rapid vaccine boosting of natural defences.
Collaborators: Dr William Bret Church (Pharmacy), A/Prof John Sullivan (Medicine), Prof Hans Zoellner (Dentistry), A/Prof Peter Williamson (SOLES, Science).
Techniques can involve: Proteomics, cell and protein fractionation, electrophoresis, immunoblotting, immunoprecipitation, multiplex-analysis. Bioinformatics, computational modelling, analysis and design of protein structures. Computational and wet laboratory studies of antibodies and antibody-binding, recombinant proteins, peptide studies and analyses; mass spectrometry, x-ray crystallisation, cryo-electron microscopy, surface Plasmon resonance.
Relevant References:
1. Lynch, G et al Seasoned adaptive antibody immunity for highly pathogenic pandemic influenza in humans. Immunol Cell Biol 90: 149-158. (2012).
2. Lynch, G.W., Selleck, P. & Sullivan, J.S. Acquired heterosubtypic antibodies in human
immunity for avian H5N1 influenza. J Mol Genet Med 3, 205-209 (2009).
3. Lynch, G.W. et al. Cross-Reactive anti-Avian H5N1 Influenza Neutralizing Antibodies in a
Normal ‘Exposure-Naïve' Australian Blood Donor Population. The Open Immunol J 1 (2008).
4. Lynch G.W et al. Imaging of High and Low Resolution Ebola Envelope GP Structures Composited with in silico Models of Difficult-to-Resolved Sections. J. Molecular & Genetic Medicine 9 (4): 186-92, 2015
The opportunity ID for this research opportunity is 2590