Helminth parasites pathways

Helminth infections have complex life cycles that involve several developmental stages within the human host. The immune response to helminth parasites involves multiple effector pathways directed against different parasite stages that generally occur simultaneously within the same host. A useful paradigm with which to understand the immune response to helminth infections, and the changes that these responses undergo over time, is to divide helminth infections into acute and chronic. 

Exploiting the knowledge that has recently developed on the induction of regulatory immune pathways by helminths, clinical trials were and are being initiated to study the effect of these parasites on inflammatory diseases. Currently, Trichuris suis is being used to treat patients with ulcerative colitis and Crohn s disease, with promising initial results [44]. Future studies are planned to examine the effect of hookworms on allergic airway diseases [45] and of T. suis on MS [11]. 

In accordance with their opportunistic way of life, parasitic flatworms have limited biosynthetic capacities as described in Introduction, they obtain many simple substrates from their hosts. More complex molecules that the parasite cannot obtain directly from the host are synthesized from these simpler building blocks. Obviously, the parasite has to synthesize complex structures like proteins and DNA. In general, the biosynthetic pathways of parasitic helminths bear a close resemblance to those of their mammalian hosts. However, the enzymes of these pathways often possess different properties, and in cases where parasites produce unique end products, there may be distinct pathway components that involve unique enzymes that are absent from the host. 

Purine and pyrimidine nucleotides are essential components of many biochemical molecules, from DNA and RNA to ATP and NAD. In recent years, the pyrimidine and especially the purine metabolism of parasitic helminths have been investigated extensively, mainly because they are different from the pathways in the mammalian host such that they have potential as targets for chemotherapeutic attack. For a review of purine and pyrimidine pathways in parasitic helminths and protozoa, see Berens et al. (1995). Although parasitic helminths do not synthesize purines de novo, but obtain them from the host, they do possess elaborate purine salvage pathways for a more economical management of this resource. Pyrimidines, on the other hand, are synthesized de novo by all parasitic flat-worms studied so far and, as with mammalian... 

Coppens, I. and Courtoy, P.J. (1996) The mevalonate pathway in parasitic protozoa and helminths. Experimental Parasitology 82, 76-85. 

Extensive work by Cheah (121, 122, 123, 128, 130), mainly with M. expansa, has shown that large cestodes possess a cytochrome chain which differs from the mammalian system in being branched and possessing multiple terminal oxidases (Fig. 5.11). One branch resembles the classical chain with cytochrome a3 as its terminal oxidase. The terminal oxidase of the alternative pathway, which branches at the level of rhodoquinone or vitamin K, is an o-type cytochrome. Cytochrome o is an autoxidisable b-type cytochrome which is commonly found in micro-organisms, parasitic protozoa and plants. The classical chain constitutes about 20% of the oxidase capacity in cestodes and cytochrome o is quantitatively the major oxidase. Cyanide-insensitive respiration - i.e. where oxygen uptake occurs in the presence of cyanide - is characteristic of most helminths (39). Cytochrome o binds cyanide much less strongly than cytochrome a3, and it seems reasonable, therefore, to equate cyanide-insensitive respiration with the non-classical pathway. 

Carbon dioxide utilisation, and the regulation of respiratory metabolic pathways in parasitic helminths. Advances in Parasitology, 13 35-69. 

Fig. 5.1. Fermentation pathways present in facultative anaerobic eukaryotes. Examples of fermentation pathways present in the cytosol and in subcellular compartments. Fermentation processes localized in hydrogenosomes (1-3) and mitochondria (4) are indicated by the shaded box. Examples of the anaerobic ATP-producing organelles shown can be found in trichomon-ads (1), chytridiomycete fungi (2), Nyctotherus ovalis (3), and parasitic helminths, bivalves and Euglena gracilis (4). CoA coenzyme A, DHAP dihydroxyacetone phosphate, Fd ferredoxin, Gly-3-P, glyceraldehyde-3-phosphate, PFO pyruvate ferredoxin oxidoreductase...

Next to fumarate reduction, some organisms use specific reactions in lipid biosynthesis as an electron sink to maintain redox balance in anaerobically functioning mitochondria. In anaerobic mitochondria two variants are known the production of branched-chain fatty acids and the production of wax esters. The parasitic nematode Ascaris suum reduces fumarate in its anaerobic mitochondria, but instead of only producing acetate and succinate or propionate, like most other parasitic helminths, this organism also use the intermediates acetyl-CoA and propionyl-CoA to form branched-chain fatty acids (Komuniecki et al. 1989). This pathway is similar to reversal of P-oxidation and a complex mixture of the end products acetate, propionate, succinate and branched-chain fatty acids is excreted. In this pathway, the... 

All helminths examined to date use at least a portion of the glycolytic pathway for energy generation (Fig. 4.1). In most parasitic helminths, hexokinase, phosphofruc-tokinase (PFK) and pyruvate kinase appear to be rate-limiting enzymes. The A. suum hexokinase has an elevated apparent for glucose (5 mM) and is much less sensitive to inhibition by glucose-6-phosphate (18). Similar observations have been made for the... 

The study of amino acid metabolism in parasites has not been conducted in a systematic manner and the overall picture is somewhat diffuse. This chapter focuses on recent findings and pathways that appear to be especially active in parasites or have unique features which distinguish the parasite s metabolism. Many of the features of helminth amino acid metabolism, for example, appear to be very similar to those of mammals and are not discussed here. An excellent review of amino acid metabolism in helminths has recently appeared (1) and further details on protozoan amino acid metabolism can be found in earlier texts (2,3). 

In many respects the basic features of amino acid and protein metabolism of parasitic protozoa and helminths resemble those of their mammalian hosts. Proteins can be broken down extracellularly or within lysosomes, and amino acids taken up and used for biosynthesis or energy metabolism. The pathways of amino acid metabolism are mostly the same as those used by animal cells. There are, nevertheless, some significant differences. Although no unique class of proteinase has been found in either protozoa or helminths, differences in specificity between parasite and host enzymes mean that inhibitors can be designed which selectively inactivate parasite enzymes. Because proteolysis is so important to many parasites at various stages of their life cycle, proteinase inhibitors are being studied and tested as potential antiparasitic agents... 

In mammals, purine ribonucleotides are synthesized de novo from amino acids, ribose, carbon dioxide and formate as well as from preformed purine bases and nucleosides through salvage pathways. The general route for de novo biosynthesis is the same in those species of mammals, birds, yeasts and bacteria that have been studied (1). Parasitic protozoans and helminths cannot synthesize purines de novo and thus rely solely on salvage pathways (2-12). 

Araujo MIAS, Hoppe B, Medeiros M Jr et al 2004 Impaired T helper 2 response to aeroallergen in helminth-infected patients with asthma. J Infect Dis 190 1797—1803 Babu S, Blauvelt CP, Kumaraswami V, Nutman TB 2006 Regulatory networks induced by live parasites impair both Thl and Th2 pathways in patent lymphatic filariasis implications for parasite persistence.] Immunol 176 3248-3256 Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL 2002 004 0025" regulatory T cells control l eishmania persistence and immunity. Nature 420 502—507 Bluestone JA, Abbas AK 2003 Natural versus adaptive regulatory T cells. Nat Rev Immunol 3 253-257... 

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