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How do protective antibodies target the Gram-negative bacterial cell wall?

Principal Supervisor: Professor Adam Cunningham, School of Immunity and Infection

Co-supervisor: Professor Ian Henderson, Institute of Microbiology and Infection

PhD project title: How do protective antibodies target the Gram-negative bacterial cell wall?

University of Registration: University of Birmingham

Project outline:

Every year antibodies binding to bacteria save millions of lives and this is the major source of protection afforded by vaccination and natural infection. However, surprisingly little is known about how antibody binds and interacts with antigens on Gram-negative bacterial surface. One reason for this is that lipopolysaccharide (LPS) and its O-antigen polysaccharide provide a barrier limiting antibody access to the surface, where they could recognize proteinaceous antigens.

This protective shield is not absolute however, as some antibodies are able to reach the bacterial surface and are protective. What makes some antigens induce protective antibody-responses while other similar antigens do not, despite both being recognised by antibodies in isolation, remains an unsolved conundrum. Answering this needs an appreciation of the properties of the antibody and the “landscape” of the bacterial surface to which it binds. Our work has made significant contributions in this area through the use of multiple approaches involving combinations of antigens and model systems. Our published and upcoming work in this area can be found in: Cunningham AF 2007 J. Immunol; Gil-Cruz C 2009 PNAS; MacLennan CA 2010 Science; Marshall J 2012 J Immunol; Wells TJ 2014 JEM; Wells TJ 2017 AJRCCM and papers that will be published shortly – Schager A 2017; Zhang Y 2017.

In this project we will build on our recent work using Salmonella as the model organism to explore this in far greater depth. The project is by its very nature highly multi-disciplinary as it cannot be approached as an immunological problem or a microbiological problem in isolation. It will therefore require a combined approach using cutting-edge super-resolution microscopy, immunology, microbiology, structural biology and modelling. This will build on our studies showing how single-base substitutions in highly conserved surface-antigens have dramatic effects on antibody-mediated protection. These studies will lead to a clearer understanding of:

  1. the structural and biophysical characteristics of the cell-envelope
  2. the nature of protective antibody-antigen interactions and
  3. how LPS and bacterial surface antigens interact dynamically to occlude epitopes and enhance antigenic diversity.

Our findings will facilitate the generation of novel, targeted vaccines and antibody-based immunotherapies against Gram-negative bacteria.

BBSRC Strategic Research Priority:  Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Super-resolution microscopy
  • Flow cytometry
  • Animal work
  • Bacterial culture
  • Protein purification
  • Structure prediction and relationships (with Vass Bavro, Essex)

Contact: Professor Adam Cunningham, School of Immunity and Infection