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Secretion of virulence determinants from Gram negative bacteria

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

The outer membrane (OM) of Gram negative bacteria is the interface between the bacterial cell and the environment. Many important virulence determinants of pathogenic bacteria are either embedded in this membrane or secreted across the membrane. The OM represents a second hydrophobic barrier through which surface proteins must be secreted and a number of different pathways, have evolved to mediate efficient surface localization from Gram negative bacteria. One common system used for export of fibrillar surface structures involved in adhesion to eukaryotic cells is the chaperone: usher system. In this pathway, a periplasmic chaperone traps and assists folding of a nascent fibrillar subunit as it is secreted across the IM. This complex is then targeted to the outer membrane translocator (or usher) where polymerization occurs to form extended surface pili or fibrillar structures. In our lab we have used assembly of the F1 fibrillar structure of Yersinia pestis as a model to understand details of the chaperone: usher system. These polymers of F1 collapse into an antiphagocytic capsule-like structure that promotes survival of the bacteria in the early stages of infection. It is also a key component of plague vaccines and detection kits. This project will use a combination of molecular, genetic and biochemical studies, complemented by collaborative structural studies, to understand the mechanism of the Y. pestis F1 assembly pathway and to optimize its vaccine potential.


Di Yu X, Dubnovitsky A, Pudney AF, Macintyre S, Knight SD, Zavialov AV. (2012) Allosteric mechanism controls traffic in the chaperone/usher pathway. Structure 20, 1861-71
Dubnovitsky, A.P.et al., Duck, Z., Kersley, J.E., Härd, MacIntyre, S. and Knight, S.D. (2010) Conserved hydrophobic clusters on the surface of the Caf1A usher C-Terminal domain are important for F1 antigen assembly. J. Mol. Biol., doi:10.1016/j.jmb.2010.08.034
Yu, X., Visweswaran, G. R., Duck, Z., Marupakula, S., MacIntyre, S., Knight, S. D., Zavialov, A. V. (2009). Caf1A usher possesses a Caf1 subunit-like domain that is crucial for Caf1 fibre secretion. Biochem. J. , 418, 541-551
Zavialov, A.V., Berglund, J., Pudney, A.F., Fooks, L. J., Ibrahim T.I., MacIntyre, S. and Knight, S.D. (2003) Structure and biogenesis of the capsular F1 antigen from Yersinia pestis: Preserved folding energy drives fiber formation. Cell 113: 587-596.
MacIntyre, S., Zyrianova, I.M., Chernovskaya, T.V., Leonard, M., Rudenko,E.G., Zav'yalov, V.P. and Chapman, D.A.G. (2001) An extended hydrophobic interactive surface of Yersinia pestis Caf1M chaperone is essential for subunit binding and F1 capsule assembly Mol. Microbiol. 39, 12-25.
MacIntyre, S., S. D. Knight, and L. J. Fooks. (2004). Structure, assembly and applications of the polymeric F1 antigen of Yersinia pestis, p. 363–408. In E.Carniel and B. J. Hinnebusch (ed.), Yersinia molecular and cellular biology.Horizon Sciences, Norfolk, United Kingdom.

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