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Dr Alex Loukas

Queensland Institute of Medical Research
300 Herston Rd, Bisbane, QLD 4006
Email: alexL@qimr.edu.au
Tel: +61-7-3845 3702
Fax: +61-7-3845 3507
Homepage: http://www.qimr.edu.au/research/labs/alexl/index.html

We have shown that aspartic proteases are expressed in the gut of hookworms where they digest haemoglobin, the major food source of the parasite. Moreover, hydrolysis was more efficient with haemoglobin from permissive hosts than haemoglobin from less-permissive hosts where the parasite can establish but does not successfully mature. With American colleagues at George Washington University in Washington, DC, we have also expressed and localized intestinal metalloproteases and cysteine proteases from hookworms, some of which are involved in a cascade of haemoglobin degradation in the parasites gut. We are pursuing the biochemistry and structural biology of these proteases with a view to developing anti-protease vaccines. We have particular expertise in the functional expression of aspartic and metalloproteases in insect cells and utility of these proteases as vaccines. All of the intestinal proteases involved in haemoglobin digestion have proved efficacious as anti-hookworm vaccines in canine trials, and some of these are being transferred to process development and GMP manufacturing for human trials over the next few years. Vaccine efficacy in animals manifests as reduced worm burdens, reduced parasite egg output, reduced pathology (effects of blood-feeding) and the generation of antibodies that neutralize proteolytic activity.
Prof Peter Hotez (George Washington University, USA) - development of a hookworm vaccine.

Prof Paul Brindley (Tulane University, USA) - helminth proteases and mobile genetic elements.

Dr Stephanie Constant (George Washington University, USA) - hookworm immune evasion.

Prof Don McManus (QIMR) - helminth proteases and vaccinology.

Dr Banchob Sripa (Khon Kaen University, Thailand) - Molecular analysis of the carcinogenic helminth parasite, Opisthorchis viverrini.

Prof David Pritchard (Nottingham University, UK) - allergens, proteases and immunomodulatory molecules of hookworms.

Dr Dave Knox (Moredun Research Institiute, UK) - nematode proteases and vaccinology.

Dr John Abbenante and Prof David Fairlie (University of Queensland) - haemoglobin cleavage by and testing of specific inhibitors against helminth proteases.

Professor John Dalton (University of Technology, Sydney) - Helminth proteases and vaccinology.

Dr Jeff Bethony (GWU) - human immune responses to hookworm proteases and secreted proteins.
Loukas A, Selzer PM, Maizels RM (1998) Characterisation of Tc-cpl-1 a cathepsin L-like cysteine protease from Toxocara canis infective larvae. Mol Biochem Parasitol 92: 275-89.

Brinkworth RI, Prociv P, Loukas A, Brindley PJ (2001) Hemoglobin-degrading, aspartic proteases of blood-feeding parasites: substrate specificity revealed by homology models. J Biol Chem 276: 38844-

Williamson AL, Abbenante G, Brindley PJ, Prociv P, Girdwood K, Berry C, Pritchard DI, Fairlie D, Hotez PJ, Dalton JP, Loukas A. (2002) Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its contribution to host-specificity. FASEB J 16: 1458-

Williamson AL, Brindley PJ, Knox DP, Hotez PJ, Loukas A (2003) Digestive proteases of blood-feeding nematodes. Trends Parasitol 19: 417-

Loukas A, Bethony JM, Williamson AL, Goud GN, Mendez S, Zhan B, Hawdon JM, Bottazzi ME, Brindley PJ, Hotez PJ (2004) Vaccination of dogs with a recombinant cysteine protease from the intestine of canine hookworms diminishes fecundity and growth of worms. J Infect Dis (in press).

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