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Professor Terry Spithill
Institute of Parasitology and FQRNT Centre for Host-Parasite Interactions
McGill University
21,111 Lakeshore Rd, Ste-Anne de Bellevue, QC. Canada. H9X 3V9
Email: terry.spithill@mcgill.ca
Tel: 1-514-398 8668
Fax: 1-514-398 7857
Homepage: http://www.mcgill.ca/parasitology/faculty/spithill/

Proteases are major virulence factors for parasites. We are studying the cathepsin L and B proteases released by the liver fluke Fasciola hepatica. We have cloned and expressed several cathepsin Ls and the major cathepsin B protease secreted by juvenile parasites. We have recently shown that the major protease released by adult Fasciola (cathepsin L5) cleaves CD4 on sheep, cattle and human T cells, and CD8 on sheep T cells, and is responsible for suppressing T cell proliferation in vitro. Using recombinant cathepsin L5, we are mapping the cleavage sites in human and ovine CD4. Functional studies will include an analysis of the cytokine expression profile of T cells, following exposure to cathepsin L5 and B1, to determine whether CD4/CD8 cleavage influences the Th0/Th1/Th2 balance of T cells. We will fully characterize other surface markers on T cells that are targets of cathepsin activity using FACS analysis. We are also studying the effects of cathepsin proteases on dendritic cells to determine whether exposure to cathepsin proteases influences dendritic cell function. The immunosuppressive action of cathepsin proteases is being assessed in mouse vaccination and infection studies.
Rob Pike (Monash)
Peter Smooker (RMIT)
Jim McKerrow (UCSF).
Wilson, L., Good, R.T., Panaccio, M., Wijffels, G.L., Bozas, S.E., Sandeman, R.M. and T.W. SPITHILL. Characterization and cloning of the major cathepsin B protease secreted by newly excysted juvenile Fasciola hepatica. Exp. Parasitol. 88: 85-94 (1998).

Smooker, P.M., Whisstock, J., Irving, J., Siyaguna, S., SPITHILL, T.W. and R.N. Pike. A single amino acid substitution affects substrate specificity in cysteine proteinases from Fasciola hepatica. Protein Sci 9: 2567-2572 (2000).

Prowse R.K., Chaplin P., Robinson H.C., SPITHILL T.W. Fasciola hepatica cathepsin L suppresses sheep lymphocyte proliferation in vitro and modulates surface CD4 expression on human and ovine T cells. Parasite Immunology 24: 57-66 (2002).

Irving, J., SPITHILL,T.W., Pike, R.N., Whisstock, J.C. and P. M. Smooker. The evolution of enzyme specificity in Fasciola spp. J Mol Evolution 57:1-15 (2003).

Law, R.H.P., Smooker, P.M., Irving, J.A., Piedrafita, D., Ponting, R., Kennedy, N.J., Whisstock, , J.C., Pike, R.N. and SPITHILL, T.W. Cloning and expression of the major secreted cathepsin B-like protein from juvenile Fasciola hepatica and analysis of immunogenicity following liver fluke infection. Inf Immun 71: 6921-32 (2003).

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