Staff Profile:Dr Sheila MacIntyre

Name:

Dr Sheila MacIntyre

Job Title:

Academic, AMS Building

Responsibilities:

Areas of Interest:

Protein secretion, pili assembly, fish pathogens.

Gram negative bacteria have evolved a number of different protein translocation pathways across the outer membrane. In recent years our research has focused on two of these pathways and the significance of the secreted products to bacterial disease.

Aeromonas salmonicida is a particularly virulent pathogen of salmonid fish. Two major secreted toxins, a glycerophospholipid:cholesterol acyltransferase and a serine protease have in the past been considered as key virulence determinants of this bacterium. We have cloned and characterised the 12 gene exe operon responsible for secretion of these and other secreted products, identified an important global regulator system – the asaI/R quorum sensing signal generator and response regulator- and identified the major sensing signal as a C4-homoserine lactone (collaboration with U. Nottingham). Serine protease production, but apparently not exe expression, was found to be under quorum sensing control. Significantly, using two different challenge models, we demonstrated that neither of the reported key toxins are essential for virulence of A. salmonicida (collaboration with SOAEFD Marine labs, Aberdeen). In the fish farming industry, this disease is currently held at bay by a combination of vaccination (based on killed bacterins), antibiotic therapy and improved husbandry. Current studies aim to target key determinants involved in the bacterium: fish host interaction with the aim of establishing the molecular basis of this poorly understood disease and ultimately improving control procedures.

The Yersinia pestis F1 protein capsule is assembled by a remarkably simple pathway involving a periplasmic chaperone, outer membrane translocator and single polypeptide subunit. Our studies have established this Caf system as a prototype for a subfamily of the chaperone:usher pathway members of which are all involved in assembly of simple bacterial adhesins (i.e. capsule or fibrillae in contrast to the complex Type I pili). Mutagenesis of the chaperone has identified the subunit binding site as a b-strand with a particularly long stretch of alternating hydrophobic residues. In analogy to the well-characterised Pap and Type I pili assembly systems, the Caf1M chaperone most likely stabilizes an incompletely folded subunit by temporarily donating this b-strand. Current studies are focused on blocking the polymerisation pathway to obtain assembly intermediates suitable for detailed structural analysis. We have also exploited the Caf system as a vector for expression of problem recombinant proteins. (Collaboration with Institute of Immunology, Lyubuchany, Russia and U. Turku, Finland). Results of this work are relevant not only to the structure of F1 capsule but also to structure and assembly of this whole subfamily of adhesins, including those produced by pathogenic E. coli and Salmonella typhimurium.

Research groups / Centres:

Microbiology research group

Publications:

Y

Jump to: 2012 | 2011 | 2010 | 2009 | 2005 | 2004 | 2003

Number of items: 8.

2012

• Yu, X. D., Fooks, L. J., Moslehi-Mohebi, E., Tischenko, V. M., Askarieh, G., Knight, S. D., MacIntyre, S. and Zavialov, A. V. (2012) Large is fast, small is tight: determinants of speed and affinity in subunit capture by a periplasmic chaperone. Journal of molecular biology, 417 (4). pp. 294-308. ISSN 1089-8638 doi: 10.1016/j.jmb.2012.01.020 (cover image)

2011

• Stuart, A., Prescott, C., MacIntyre, S., Sethar, A., Neuman, B., McCarthy, N. D., Wimalarathna, H. and Maiden, M. C. J. (2011) The role of rodents as carriers of disease on UK farms: a preliminary investigation. In: 8th European Vertebrate Pest Management Conference, 26-30 September 2011, Berlin, Germany, pp. 198-199. (In Press) (Proceedings of the 8th European Vertebrate Pest Management Conference)

2010

• Dubnovitsky, A. P., Duck, Z., Kersley , J. E., Hard, J. E., 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. Journal of Molecular Biology, 403 (2). pp. 243-259. ISSN 0022-2836 doi: 10.1016/j.jmb.2010.08.034

2009

• Yu, X., Visweswaran, G. R., Duck, Z., Marupakula, S., MacIntyre, S., Knight, S. D. and Zavialov, A. V. (2009) Caf1A usher possesses a Caf1 subunit-like domain that is crucial for Caf1 fibre secretion. Biochemical Journal, 418. pp. 541-551. ISSN 0264-6021 doi: 10.1042/bj20080992

2005

• Zavialvo, A. V., Tischenko, V. M., Fooks, L. J., Brandsdal, B. O., Aqvist, J., Zav'Yalov, V. P., MacIntyre, S. and Knight, S. D. (2005) Resolving the energy paradox of chaperone/usher-mediated fibre assembly. Biochemical Journal, 389. pp. 685-694. ISSN 0264-6021

2004

• MacIntyre, S., Knight, S.D. and Fooks, L.J. (2004) Structure and function of F1 capsule. In: Carniel, E. and Hinnenbusch, J. (eds.) Yersinia: Molecular and Cellular Biology. Horizon Bioscience, pp. 363-407. ISBN 9781904933069

2003

• Zavialov, A. V., Berglund, J., Pudney, A. F., Fooks, L. J., Ibrahim, T. M., 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 (5). pp. 587-596. ISSN 0092-8674 doi: 10.1016/S0092-8674(03)00351-9
• Gunasena, D. K., Komrower, J. R. and MacIntyre, S. (2003) The fish pathogen Yersinia ruckeri possesses a TTS system. Advances in Experimental Medicine and Biology, 529. pp. 105-7. ISSN 0065-2598 doi: 10.1007/b100541

This list was generated on Fri May 25 07:31:34 2012 BST.

 

Other publications

Kersley, J., Zavialov, A. V., Moslehi, E. , Knight, S. D. and MacIntyre, S. (2003) Mutagenesis elucidates the assembly pathway and structure of Yersinia pestis F1 polymer Adv Exp Med Biol 529: 113-116

Zavialov, A.V. Kersley, J., Korpela, T., Zav'yalov, V.P., MacIntyre, S. and Knight, S. (2002) Donor strand complementation mechanism in the biogenesis of non-pilus system. Mol. Microbiol. 45, 983-995

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.