A Helminth is a parasitic worm and fits into the category of eukaryotic parasites, a parasite is a disease-causing organism that lives in or on animals and derives its nourishment from its host, it benefits at the expense of the host. They cause a wide variety of infectious diseases' and weaknesses, and some of these can cause serious harm or even death. Helminths may be classified into four categories, monogeneans, nematodes (roundworms), trematodes (flatworms) and cestodes (tapeworms).
Helminth eggs can be found in food, water, air, feces, pets and wild animals, and many surfaces. The majority of the time the eggs have to enter the animal's body in order to infect them, the pathways they use are the nose, through the mouth or the anus. Schistosomes and nematodes like hookworms and Strongyloides can pierce the skin to enter the body. Wuchereria, Onchocerca, and Dracunculus areÂ transmitted by flies and mosquitoesÂ whilst they are feeding on the animals. The most common infectious worm in humans is the intestinal worm (or geohelminth) which is soil-transferred, it is most prominent in disadvantaged communities through the use of contaminated water used for drinking and cooking as a result of inadequate water treatment (Charity Water 9). The most predominant of geohelminth infections are those which are caused by infections withÂ Ascaris lumbricoides,Â Trichuris trichiura, and hookworm (Â Necator americanus and Ancylostoma duodenale), and infect an estimated 2 billion humans (Savioli L 8).
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A Protease, also known as proteolytic enzymes, peptidase or proteinase refers to a group of enzymes which perform proteolysis which is a process used to break down proteins into amino acids or peptides. Proteases are different mainly in their skill to break down a range of peptide bonds. Each type of protease has a specific kind of peptide bond that it breaks. There are currently 6 different types of peptides which are classified into broad groups, these are Serine proteases, Threonine proteases, Cysteine proteases, Aspartate proteases, Metalloproteases and Glutamic acid proteases. We will be focusing on Cysteine proteases as these have a major role in helminth parasites. There are 2 major families of cysteine proteases, one of them is Caspase which is cytosolic, they have a role in cell death (apoptosis) and are asparate-specific, the other is Cathepsin, which is usually active under acidic conditions, mainly found in lysosomes and is a key part in protein degradation.
Cathespins play a vital role in all animals and a lot of other organisms; they are enzymes which degrade proteins known as proteases. Many different types of Cathepsins have been found and so far we know of 15, these are notable by the types of proteins that they cleave, the structure of them and their catalytic mechanisms. They were first discovered in the early 20th century. One of the first to be found was Cathepsin C,Â (also known as dipeptidyl peptidase I or DPPI), in the 1940s (Gutman and Fruton, 1948). The next to be found were in the early 1970's, these were cathepsin B and cathepsin H.
The current 15 Cathepsins that we know of can be categorised centred on their structure and catalytic type into serine (cathepsins A and G), aspartic (cathepsins D and E), and cysteine cathepsins. "The largest cathepsin family are Cystine cathepsins, with 11 proteases in humans referred to as clan CA, family C1a: cathepsins B, C (also known as cathepsin J and dipeptidyl-peptidase 1), F, H, K (also known as cathepsin O2), L, O, S, W, V (also known as cathepsin L2), and Z (also known as cathepsin X and cathepsin P)" (Rawlings ND 4). All of these have different roles, from Cathepsin A which connects with lysosomal enzymesÂ to make a complex of high-molecular-weight multimers which provides a protective role for stability and activity, Deficiencies in this protein are linked to multiple forms of galactosialidosis to Cathepsin C which seems to have a key role in activating manyÂ serine proteasesÂ in inflammatory cells in order to create an immune response, In humans, it is encoded by theÂ CTSCÂ gene (Â Paris A 1995). Mutations in the cathepsin C gene (CTSC)Â can lead to Papillon Lefèvre syndrome (PLS) which is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe periodontitis (Y. Zhang).
The link between both cathepsin and helminth parasites is that cathepsins play a major role in all helminths; they function in virulence, entry into the host, tissue migration and the repression of host immune responses (Robinson MW 10). In the helminth Haemonchus contortus, Cathepsin B-like enzymes appear to digest host proteins in order to acquire nutrients. The main cathepsin expressed in Fasciola hepatica helminths is cathepsin L1 (FhCL1) , it is synthesized within the gastrodermal epithelial cells of the parasite and are kept in specialised secretory vesicles as inactive zymogens (Collins, P.R. et al, 18). It is the major cysteine protease that is secreted by the parasite which has a pivotal role in various aspects of its pathogenicity. For example, the protease takes part in acquiring nutrients by breaking down host proteins to smaller more absorbable peptides (Tort, J 5), it enables the passage of the parasite through the hosts intestine and liver by cleaving interstitial matrix proteins such as fibronectin, laminin, and native collagen (Berasain, P, 6) and is linked with the inactivation of host immune defenses by cleaving immunoglobulins (Smith, A, 7).
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Molecules that are secreted by helminths called their secretome have often got Cathepsin L, F and B proteases found within it, this allows them to carry out their roles in parasite-host interactions like enabling tissue penetration and disarming the soluble and cellular arms of the host immune system (Robinson, M.W. et al 16)
Cathepsin C on the other hand functions in the breakdown of peptide products and macromolecules that are broken down in the gut lumen and absorbed into the gastrodermis (Dalton, J.P. et al, 17), more breakdown of aminopeptides occurring in the same cells result in the release of free amino acids which are then used for growth and development of the parasite.In the Schistosoma mansoni it uses cathepsin B1 which is found in the worms gut to catalyse the degradation of the host's proteins.
Diplostomum pseudospathaceum has cysteine proteinase which are located in the cercarial penetration glands and it is thought to be involved in skin penetration of aquatic birds (MoczoÅ„, 1994, 15)
The helminth parasite, Liver fluke (Fasciola hepatica) which is in the group of trematodes is one of the main causes of fasciolosis, this is a disease which can lead to liver failure and limits the growth as well as milk and meat production of infected sheep and cattle worldwide. Recently, worldwide losses in animal productivity due to fasciolosis were estimated at over US$3.2 billion per annum (Â Spithill 11). There have been recent reports that these liver flukes are becoming resistant to anthelmintics such as triclabendazole which is the main drug for the treatment of fasciolosis and so it is essential to get an effective vaccine which will work against the parasite, a logical approach to the development of new drugs would be to find new targets capable of disturbing the physiology of the liver fluke.
Cysteine endopeptidases has an important role in fasciolosis in sheep and for this reason a derivative of E-64, namely, Ep-475 which is a cysteine protease inhibitor was tested to see if it had a valuable effect as potential inhibitor of liver fluke cysteine protease activities in the parasite's natural host, therefore affecting liver fluke fecundity, egg viability, parasite size, and burden. The results from this experiment were promising, although this did not decrease the amount of liver flukes present within the animals that were tested (sheep), it did show a significant decrease in the average size of the flukes and when these were stained and observed they found underdeveloped reproductive structures and "shoulders". It also decreased the amount of eggs that were being produced as well as the viability of them. The ultimate finding of ths study is that Ep-475 can offer some degree of protection by affecting fecundity, the size of the parasite and its ability to embryonate. Also, considering that the spread of fasciolosis is mainly by the contamination of grasses which the animals consume with viable eggs, the effects that a protease inhibitor has in decreasing the fertility of the parasites might prevent the spread of disease and therefore reduce the frequency of fasciolosis in endemic areas. This would be one way to decrease the effect that Fasciola hepatica has on domesticated animals but recently there has been constant pressure from the consumers to decrease the drug residues in the food chain, this makes anthelmintics a less attractive option for control of fasciolosis. There have been a few proteins from F. hepatica which have shown potential as vaccine candidates (McManus DP 12) including cathepsin L1.
Vaccine trials have been carried out using native FhCL1 and these have shown that this molecule can generate reductions in the amount of flukes of 55-72%, following experimental challenge in cattle and sheep (Dalton JP, 13). As well as reducing the fluke number, less flukes developed to maturity in vaccinated animals than in controls. A notable loss in egg production was also seen in these trials (55-98%) and those that were produced showed a lower viability on hatching assays (Mulcahy G,14). This would also lead to a reduction in pasture contamination which would mean less animals would be infected the following year.
Helminth parasites are the cause of a lot of disease all over the world from the tropics to the more temperate climates, the worst of all of these disease' is malaria which is the cause of the most deaths globally. It kills around 1 million people each year and these are mainly young children in sub-Saharan Africa. They also infect animals and cause a lot of death, this affects domesticated animals and the and the worldwide losses in animal productivity due to a disease caused my the liver fluke fasciolosis were estimated at over US$3.2 billion per annum. We know that cathepsins play a major role in helminths in how they enter the hosts body and move through the intestines and liver to how they are able to cause the inactivation of the hosts immune defences, with this knowledge we could create a vaccine that would target
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these areas and prevent the process from happening which in turn would lead to the death of the helminth and so create immunity to them.