A Dominant Role for Extracellular Glutathione S -Transferase from Onchocerca volvulus Is the Production of Prostaglandin D ₂

Abstract

The extracellular glutathione S-transferase from the filarial parasite Onchocerca volvulus (Ov-GST1) is a glutathione-dependent prostaglandin D synthase. Ov-GST1, located in the outer hypodermal lamellae and in parts of the cuticle, produces prostaglandin D 2 directly at the parasite-host interface. Ov-GST1 therefore has the potential to participate in the modulation of the host immune response by contributing to the production of prostanoids; this supports the predominant hypothesis that parasite-derived eicosanoids influence host inflammatory and immune cells.Onchocerciasis, caused by the filarial nematode Onchocerca volvulus, affects 18 million people in sub-Saharan Africa. This chronic disease is entirely caused by microfilarial stages. The resulting immunopathological changes, which can lead to severe dermatitis and blindness, reflect the close relationship between the parasite and the immunological mechanisms of the host. Eosinophils, elevated levels of serum immunoglobulin E (IgE) and IgG4, and mast cell proliferation have been shown to be associated with infections caused by filarial parasites, indicating a pronounced bias toward Th2 responses. Whether this Th2 response is protective or is present to amend the Th1 pathology is still a matter of debate (12; Special program for research and training in tropical diseases, final report series 27, http://www.who.int/tdr /research/finalreps/no27.htm, 2000). However, the long-term survival of the parasites in the host despite their close proximity to inflammatory and immune cells is remarkable and has initiated a search for parasite-derived molecules that are involved in the modulation of host immune responses.Eicosanoids are lipid mediators that are produced from polyunsaturated fatty acids, most notably arachidonic acid. The conversion of arachidonic acid to prostanoids is catalyzed by cyclooxygenase (COX) and leads to the formation of the unstable hydroxyl endoperoxide prostaglandin (PGH 2 ). By the action of specific PG synthases, PGH 2 is converted to PGF 2␣ , PGE 2 , and PGD 2 .Glutathione S-transferases (GSTs) are multifunctional enzymes that are involved in the biotransformation of xenobiotics and endogenously derived cytotoxic compounds, displaying a broad specificity for hydrophobic electrophilic compounds. Molecular evolutionary studies revealed that the hematopoietic (spleen-type) PGD synthase belongs to the sigma GST class (6). This enzyme exclusively occurs in antigen-presenting, dendritic, Langerhans, Kupffer, megakaryoblastic, and mast cells, suggesting that it functions in the production of PGD 2 as an allergic and inflammatory mediator (22). Our previous studies of the O. volvulus GST1 (Ov-GST1) demonstrated an overall sequence homology of 47% with the hematopoietic PGD synthase, clearly showing that the enzyme belongs to the sigma class. However, Ov-GST1 displays unique structural features: it has a signal peptide and a 25-amino-acid N-terminal extension before sequence identity to the sigma class GSTs begins. Ov-GST1 is located in the outer ...

Molecular evidence for apoptosis in microfilariae of Wuchereria bancrofti induced by diethylcarbamazine

“…There are substantial information that DEC blocks a number of steps in both cyclooxigenase (COX) and lipoxigenase pathways, including inhibition of leucocyte chemotaxis, granulocyte degranulation, and peripheral vasodilation (Maizels and Denham 1992). Filarial parasites also synthesize and release prostanoids, particularly prostacyclin and PGE2, which are vasodilators and potent platelet anti-aggregatory factors (Liu et al 1990; Liu and Weller 1992;Sommer et al 2003). Moreover, KanesaThasan et al (1991) demonstrated that DEC severely inhibits the synthesis of microfilariae cyclooxigenase products.…”

Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems

“…GSTs in general are multifunctional enzymes found in both invertebrates and vertebrates, and it is unlikely that all of the sigma-class forms will have PG synthase activity because some lack the amino acid residues involved in substrate (PGH 2 ) binding (Thomson et al, 1998). Recently, however, both the sigma class GSTs from the filarial parasite Onchocerca volvulus (Sommer et al, 2003) and Schistosoma (Johnson et al, 2003) have been shown to convert PGH 2 to PGD 2 , while in Ascaridia galli a purified GST has PGE synthase activity (Meyer et al, 1996). In the case of the O. volvulus GST (Ov-GST-1), this enzyme is located at the margins of the parasite, in the cuticle and hence in a prime location to influence the host responses.…”

Control of inflammatory diseases by pathogens: lipids and the immune system

“…Parasites not only induce prostaglandin production by the host to suppress the immune response, but also are able to produce prostaglandins themselves. Schistosomes were shown to secrete PGD2, thereby inhibiting the migration of Langerhans cells upon exposure to schistosome cercariae [31], and Onchocerca volvulus was shown to express glutathione S-transferase on its surface that produces PGD2 directly at the hostparasite interface [32]. The question regarding helminths is whether PGD2 production is involved in controlling anti-parasitic responses, which would justify the investment made by helminths to elaborate such antiinflammatory molecules.…”