Royal Society University Research Fellow
Description of research
1. Host-pathogen interactions during Shigella infection
Diseases caused by bacteria, viruses and other parasites are major causes of death, disability, and social and economic disruption for millions of people. Our ability to effectively treat infectious diseases is being progressively depleted due to increasing resistance of microbes to antimicrobial drugs. A top priority today is the development of new low-cost drugs that can replace those that are becoming ineffective. An essential part of developing new therapeutics is a clear molecular understanding of how pathogens evade our immune defences and hijack our cellular components.
Our research focuses on the bacterial pathogen Shigella flexneri. This pathogen invades cells of our digestive tract and hijacks components of the actin polymerization pathway in order to aid its movement within our cells and allowing it to spread directly from cell to cell. In this way Shigella can limit its detection by our immune system. As an extra defence S. flexneri produces proteins that specifically disarm the intracellular immune response to pathogens. We study the structure, interactions and regulation of Shigella virulence proteins and the host proteins they target.
2. Molecular Mechanism of Krabbe Disease
In collaboration with the laboratories of Prof. Read and Prof. Luzio in the CIMR and Prof. Cox in the Dept of Medicine we are studying how clinically-identified mutations of the enzyme galactocerebrosidase (GALC) result in Krabbe disease, a devastating neurodegenerative disorder. Our recent structure of GALC has provided new insight into the molecular role of pathogenic mutations and allowed us to identify patients that might be responsive to a new form of therapy known as pharmacological chaperone therapy.
Keywords: Galactocerebrosidase, Shigella flexneri, Type III Secretion
Clinical conditions: Krabbe Disease, Shigellosis
Methodologies: Biochemistry, biophysics and structural biology
Prof. Randy Read, Prof. Timothy Cox
Dr Henrik Jensen, Aarhus University, Denmark
Deane, J.E., Graham, S.C., Kim, N.N., Stein, P.E., McNair, R., Cachón-González, M.B., Cox, T.M. and Read, R.J. (2011) “Insights into Krabbe Disease from the Structures of Galactocerebrosidase.” Proc. Natl Acad. Sci. U.S.A.108:15169-73
Deane, J.E., Abrusci, P. Johnson, S. and Lea, S.M. (2010) “Timing is Everything: the regulation of type III secretion.” Cell. Mol. Life Sci. 67: 1065-75.
Schneider, M.C., Prosser, B.E., Caesar, J.J., Kugelberg, E., Li, S., Zhang, Q., Quoraishi, S., Lovett, J.E., Deane, J.E., Sim, R.B., Roversi, P., Johnson, S., Tang, C.M. and Lea, S.M. (2009) “Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.” Nature 458: 890-3.
Deane, J.E., Graham, S.C., Mitchell, E.P., Flot, D., Johnson, S. and Lea S.M. (2008) “Crystal structure of Spa40, the specificity switch for the Shigella flexneri type III secretion system” Mol. Micro. 69: 267-76.