International Protease Network

Institute of Parasitology
McGill University
21,111 Lakeshore Road, Sainte Anne de Bellevue QC H9X 3V9
Email: john.Dalton@mcgill.ca
Tel: (514) 398 8668
Fax: (514) 398 7857
Homepage: www.mcgill.ca/parasitology

Research

Our research focuses on the understanding of the biology and biochemistry of parasitic organisms, and on the interplay between parasites and their hosts. In particular, I am interested in the molecules that parasites release to alter the physiology of their hosts. Of critical importance is how parasites manipulate host immune responses to their advantage. While many aspects of this research are basic, the ultimate goal is the discovery of a strategy(s) by which we can protect animals and humans from parasitic infections by either chemotherapeutic (drugs) or immunological (vaccines) means.
More specifically, in my research on malaria (Plasmodium sp.) we have identified several aminopeptidase enzymes which the parasites employ to release amino acids from haemoglobin within erythrocytes. Research on the Schistosoma sp., the causative agents of tropical disease schistosomiasis in animals and humans, has led to the isolation and characterisation of a battery of enzymes that the parasite employs to systematically degrade haemoglobin from host red blood cells which they use as nutrient. Research on liver fluke disease (Fasciola hepatica) has characterised a number of proteolytic enzymes that the parasite uses to penetrate tissue and to obtain nutrients from the host. Other molecules, such as the anti-oxidants, peroxiredoxins, are involved in detoxifying ROS derived from parasite metabolism or by immune effector cells. Our recent studies have demonstrated a role for cathepsin Ls and peroxiredoxin in modulating the host’s innate immune mechanisms. Recombinant forms of these enzymes are in experimental trials as vaccines against liver fluke infection of ruminants.

Collaborations

Dr. Grace Mulcahy, Department of Microbiology and Parasitology, Faculty of Veterinary Medicine, UCD.
Dr. Sean Doyle, Biology Dept., Biology Department, National University of Ireland, Kildare, Ireland.
Dr. Sandra O’Neill, School of Nursing, Dublin City University, Ireland
Dr. Angus Bell, Microbiology Department., The Moyne Institute, Trinity College Dublin.
Prof. Paul Brindley, Tulane School of Medicine, New Orleans, LA.
Dr. Alex Loukas, Queensland Institute for Medical Research, Qld, Australia.
Dr. Patrick Skelly, Harvard School of Public Health, MA, USA.
Dr. John Adams, School of Biology, University of Notre Dame, Indiana, USA.
Prof. Aaron Maule, Biochemistry Department, Queens University Belfast, N. Ireland.
Dr. Linda S. Brinen, Cellular & Molecular Pharmacology, Sandler Center for Basic Research in Parasitic Diseases, University of California San Francisco, CA 94143-0511.

Publications

Robinson MW, Menon R, Donnelly SM, Dalton JP, Ranganathan S (2009). An integrated transcriptomic and proteomic analysis of the secretome of the helminth pathogen, Fasciola hepatica: proteins associated with invasion and infection of the mammalian host. Mol Cell Proteomics. May 14. [Epub ahead of print]

Rinaldi G, Morales ME, Alrefaei YN, Cancela M, Castillo E, Dalton JP, Tort JF, Brindley PJ. (2009) RNA interference targeting leucine aminopeptidase blocks hatching of Schistosoma mansoni eggs. Mol Biochem Parasitol. May 19. [Epub ahead of print].

Maric S, Donnelly SM, Robinson MW, Skinner-Adams T, Trenholme KR, Gardiner DL, Dalton JP, Stack CM, Lowther J. The M17 leucine aminopeptidase of the malaria parasite Plasmodium falciparum: the importance of active site metal ions in the binding of substrates and inhibitors. Biochemistry. 2009 May 1. [Epub ahead of print]

Lowther, J., Robinson, M.W., Donnelly, S.M., Xu, W., Stack, C.M, Matthews, J.M., Dalton, J.P. (2009). The Importance of pH in Regulating the Function of the Fasciola hepatica Cathepsin L1 Cysteine Protease. PLoS Negl Trop Dis. 2009;3(1):e369.

McGowan, S, Porter, C.J, Lowther, J., Stack, C.M., Golding, S.J., Skinner-Adams, T.S., Trenholme, K.R., Teuscher, F., Donnelly, S.M., Grembecka, J., Mucha, A., Kafarski, P., DeGori, R., Buckle, A.M., Gardiner, D.L., Whisstock, J.C., Dalton, J.P. (2009). Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutralaminopeptidase: a new route for antimalarial compounds. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2537-42.

Pinlaor, P., Kaewpitoon, N., Laha, T., Sripa, B, Kaewkes, S., Morales, M.E., Mann, V.H, Parriott, S.K., Suttiprapa, S., Robinson, M.W., To, J., Dalton, J.P., Loukas, A. and Brindley, P.J. (2009) Cathepsin F cysteine protease of the human liver fluke, Opisthorchis viverrini: phylogenetic relationships, gene structure, and functional characterization. PLoS Negl Trop Dis. 2009;3(3):e398.

Dalton, J.P., Brindley, P.J., Donnelly, S.M. and Robinson, M.W. (2009) The enigmatic asparaginyl endopeptidase of helminth parasites. Trends in Parasitology 25(2):59-61.

Stack, C.M, Caffrey, C.R., Donnelly, S.M., Seshaadri, A, Lowther J., Tort, J.F., Collins, P.R., Robinson, M.W., Xu, W, McKerrow, J.H., Craik, C.S., Geiger, S.R., Marion, R., Brinen, L.S. and Dalton, J.P. (2008) Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica. J. Biol. Chem. 283, 9896-9908.

Robinson, M.W., Tort, J.F., Lowther J., Donnelly, S.M., Wong. E., Weibo, Xu., Stack C.M. Padula, M., Herbert, B., and Dalton, J.P. (2008) Proteomic and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen, Fasciola hepatica: expansion of a repertoire of virulence-associated factors. Mol. Cell. Proteom. 7, 1111-1123.

Robinson, M.W., Dalton, J.P. and Donnelly, S.M. (2008). Helminth pathogen cathepsin proteases: it’s a family affair. Trends in Biochemical Sciences 33, 601-608.