Chapter 4 Peptidases of Trematodes
Introduction
Trematodes are members of the phylum Platyhelminthes (or flatworms). Within this phylum the species of veterinary and medical importance belong to the sub‐class Digenea.1 These digenean trematodes represent a rich group of around 18,000 species parasitizing all classes of vertebrates (Cribb et al., 2001) and impairing almost all tissues of vertebrate body (Mehlhorn, 2001). At least 118 trematode species belonging to 20 families are causative agents of human infections, affecting significant proportions of the population in many countries (e.g. Ashford and Crewe 1998, Hotez et al., 2006, World Health Organization, 2004).
Flukes of the genus Schistosoma (family Schistosomatidae) are important in terms of human medicine as causative agents of human schistosomiasis as the disease leads to 11,000 deaths per year, although this number may be an under‐estimation.2 Over 200 million people are infected with 500–800 million people living at risk (Molyneux, 2006, Muller, 2002, Steinmann et al., 2006, World Health Organization, 2001, World Health Organization Expert Committee, 2002).3
There are also other globally important groups of zoonotic trematodes (e.g. the fasciolids, family Fasciolidae). The number of animals infected by Fasciolidae has been estimated at 600–700 million with the annual economic loss in cattle and sheep stocks around $2.0–3.2 billion. Fascioliasis has emerged as a significant zoonosis in several countries, including Bolivia, Peru, Ecuador, Iran, Turkey and Egypt (McManus and Dalton, 2006, Rinaldi et al., 2008, Spithill et al., 1999).4
Digenetic trematodes have complex life strategies, involving changes between asexually and sexually reproducing developmental stages that are found in the intermediate hosts (mostly snails) and the definitive hosts (many vertebrate species), respectively. Besides other important molecules produced by flukes (e.g. eicosanoids causing local immunosuppression or vasodilatation, carbohydrates serving for molecular mimicry), proteins in general, and peptidases in particular, play a number of pivotal roles during the lifecycle of each trematode species.5 Trematode peptidases have been identified as essential enzymes of immature (larval) as well as mature (adult) stages (Cesari et al., 2000, Dalton and Brindley, 1997, Dvořák et al., 2005, Sajid et al., 2003). They are critical to many host–parasite interactions such as invasion, migration through the tissues, degradation of nutritional proteins (e.g. haemoglobin), immune evasion, activation and modulation of inflammation (Caffrey et al., 2004, Delcroix et al., 2007, Donnelly et al., 2006, He et al., 2005, Horák and Kolářová, 2005, Horák et al., 2008, Koehler et al., 2007, McKerrow et al., 2006, Trap and Boireau, 2000). The necessity of peptidases for trematode survival places these molecules as prime targets for the development of new drugs (e.g. cysteine peptidase (CP) inhibitor K11777; Abdulla et al., 2007, McKerrow et al., 2006) or as components of molecular vaccines (e.g. cathepsins L1 and L2 of Fasciola hepatica; McManus and Dalton, 2006).
Several powerful sources accumulating and cataloguing information on enzymes of organisms are available for trematodologists dealing with peptidases (e.g. MEROPS—the peptidase database, http://merops.sanger.ac.uk/, Rawlings et al., 2008; BRENDA—the comprehensive enzyme information system, http://www.brenda‐enzymes.info/; Chang et al., 2009; UniProt(KB)—central access point for extensive curated protein information, www.uniprot.org; The UniProt Consortium, 2008; or the Handbook of Proteolytic Enzymes, Vol. 2.; Barrett et al., 2004). Although the MEROPS, BRENDA or UniProt(KB) databases comprise information on peptidases in general, specific views and links to parasites (trematodes) are often incomplete. In contrast, the second edition of the Handbook of Proteolytic Enzymes, though containing comprehensive descriptions of peptidases of parasitic organisms, was published back in 2004. At present, a rapid application/introduction of new techniques in life sciences (e.g. genome database data mining, micro‐array analysis or biotransformation) yields a continuous influx of data. Therefore, an up‐to‐date review of trematode peptidases of great importance for medical and veterinary parasitology is now warranted. This present review contains up‐to‐date information on trematode peptidases (molecular biology, biochemistry, biology, etc.) as a stimulus for further activities in the research of these key molecules and their role in host–parasite interactions.
Section snippets
General Classification of Peptidases
Peptidases are usually summarized according to the three main criteria: ‘place of action’ within the peptide/protein substrate, mechanism of catalysis and molecular structure. In general peptidases catalyze hydrolysis of peptide bonds, but the position or ‘where they act’ is different: ‘inside’ (endo‐)/‘outside’ (exo‐) or in particular position of the polypeptide chain (Table 4.1). The mechanism of catalysis is determined by chemical properties of side groups of the amino acids (AAs) that
Peptidases of Trematodes—Brief History of Research
Because of their central functions in cellular biology and their potential medical and industrial application peptidases have been interesting subjects of many branches of science for decades. Of course, peptidases became attractive molecules also in the fields of parasitology, including trematodology, since they play important roles in acute and chronic phases of many parasitic diseases (e.g. schistosomiasis, malaria, leishmaniasis, Chagas disease and African sleeping sickness McKerrow et al.,
Peptidases of Trematodes—Current Status
In this article, we review trematode peptidases with respect to their biological roles, biochemical and molecular properties, and their possible use as effective vaccine components or immunodiagnostic markers of diseases caused by trematodes.11
Conclusion
Trematodiases are a significant group of diverse parasitic diseases of global medical and veterinary importance. The need for novel anti‐trematode drugs/vaccines, not least for treatment/prevention of schistosomiasis, requires participation and co‐operation of specialized research teams in all over the world, and continuous support from funding agencies (both public and philanthropic) to orchestrate these endeavours. This review has attempted to present a timely discussion of the salient points
Acknowledgements
The research of Petr Horák, Libor Mikeš, Martin Kašný, Vladimír Hampl and their students has recently been supported by the Czech Science Foundation (Grant No. 206/07/0233 and 206/09/H026) and the Czech Ministry of Education (Grant No. MSM 0021620828 and MSM LC06009).
Conor R. Caffrey and Jan Dvořák are supported by the Sandler Foundation.
John P. Dalton is currently supported by the National Health and Medical Research Council of Australia Project (Grant No. 352912) and he is a recipient of a
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