Intravascular filarial parasites elaborate cyclooxygenase-derived eicosanoids (original) (raw)
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Eicosanoids in parasites and parasitic infections
Advances in parasitology, 2000
Eicosanoids are lipid mediators with multiple functions in vertebrate tissues and invertebrate organisms. In this review the roles of eicosanoids--mostly prostaglandins (PGs), thromboxanes and leukotrienes--in parasite physiology and host-parasite interactions are discussed. PGs are present in the saliva of blood-sucking arthropods facilitating feeding by increasing local blood flow and prolonged attachment of ticks by immune suppression. Release of various eicosanoids has also been demonstrated for a number of protozoan and metazoan endoparasites. These substances appear to play a role in penetration, immune suppression, inflammation or modulation of haemostasis, enabling parasite invasion and establishment. Moreover, endogenous eicosanoids serve various functions in parasite metabolism and physiology. In many parasitic infections eicosanoids are involved in host pathology, e.g. granuloma formation, coagulopathy, secretory diarrhoea, or fever. Immune suppression by induction of PG ...
Acta Tropica, 2009
Prostaglandins generated by multiple tissue and immune cells exhibit regulatory effects on the vascular and immune systems. Prostaglandin E 2 (PGE 2 ), in particular, affects innate as well as adaptive immune mechanisms. We identified PGE 2 in host immune cells adjacent to Onchocerca volvulus in subcutaneous onchocercomas and the affected skin. Using immunohistology, PGE 2 was predominantly detected in infiltrating macrophages but also in plasma cells. Consecutive sections revealed concomitant presence of PGE 2 and transforming growth factor-beta (TGF-beta), representing a second immunoregulative mediator in macrophages and plasma cells. TGF-beta was preferentially observed in the infiltrating macrophages in patients with a generalized hyporeactive onchocerciasis and less in patients with the hyperreactive form. The presence of PGE 2 and TGF-beta in adjoining host cells infiltrating in the onchocercoma and dermis may indicate containment of inflammatory responses that could favour survival of the filarial parasite.
PloS one, 2016
Helminth parasites remain a major constraint upon human health and well-being in many parts of the world. Treatment of these infections relies upon a very small number of therapeutics, most of which were originally developed for use in animal health. A lack of high throughput screening systems, together with limitations of available animal models, has restricted the development of novel chemotherapeutics. This is particularly so for filarial nematodes, which are long-lived parasites with a complex cycle of development. In this paper, we describe attempts to visualise the immune response elicited by filarial parasites in infected mice using a non-invasive bioluminescence imaging reagent, luminol, our aim being to determine whether such a model could be developed to discriminate between live and dead worms for in vivo compound screening. We show that while imaging can detect the immune response elicited by early stages of infection with L3, it was unable to detect the presence of adul...
The Journal of Immunology, 2001
Parasite survival and host health may depend on the ability of the parasite to modulate the host immune response by the release of immunomodulatory molecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein of the rodent filarial nematode Acanthocheilonema viteae, and has homologues in human filarial nematodes. Previously we have shown that ES-62 is exclusively associated with a Th2 Ab response in mice. Here we provide a rationale for this polarized immune response by showing that the parasite molecule suppresses the IFN-␥/LPS-induced production, by macrophages, of bioactive IL-12 (p70), a key cytokine in the development of Th1 responses. This suppression of the induction of a component of the host immune response extends to the production of the proinflammatory cytokines IL-6 and TNF-␣, but not NO. The molecular mechanism underlying these findings awaits elucidation but, intriguingly, the initial response of macrophages to ES-62 is to demonstrate a low and transient release of these cytokines before becoming refractory to further release induced by IFN-␥/LPS. The relevance of our observations is underscored by the finding that macrophages recovered from mice exposed to "physiological" levels of ES-62 by the novel approach of continuous release from implanted osmotic pumps in vivo were similarly refractory to release of IL-12, TNF-␣, IL-6, but not NO, ex vivo. Therefore, our results suggest that exposure to ES-62 renders macrophages subsequently unable to produce Th1/proinflammatory cytokines. This likely contributes to the generation of immune responses with an antiinflammatory Th2 phenotype, a well-documented feature of filarial nematode infection.
Clotting Factors and Eicosanoids Protect against Nematode Infections
Journal of Innate Immunity, 2011
are amongst the best-conserved clotting factors and help to sequester bacteria at the wound site in both insects and humans. Recent evidence for an immune function of TG derives from an infection model that involves insect pathogenic nematodes and their symbiotic bacteria [6]. Infection with nematodes such as Heterorhabditis bacteriophora involves the release of symbiotic bacteria (Photorhabdus luminescens) from the gut, which helps the nematode to suppress host immunity and eventually kill the host [7]. Genetic studies in Drosophila show that despite the fact that antimicrobial peptides are induced in Heterorhabditis/Photorhabdus-infected hosts, both major pathways of immune induction (Toll and imd) appeared dispensable for the response against the nematodes and their bacteria [8]. We have previously shown that TG plays a role in the defense against Heterorhabditis/Photorhabdus; Drosophila larvae with reduced TG levels were more sensitive to nematode infections [6]. Upon contact with Photorhabdus, hemolymph TG targets microbial surfaces, leading to the deposition of small aggregates (microclots). Here, we screened clotting factors other than TG for their effects during a Heterorhabditis/Photorhabdus infection. We provide further evidence for an immune function of the clot and show that eicosanoids, which are required during blood clotting [9] , also regulate the response against nematodes and their bacteria.
… and Physiology Part A: …, 1997
- Nodulation is the first, and qualitatively predominant, cellular defense reaction to bacterial infections in insects and other invertebrates; 2) treating silkworms, Bombyx mori, with the eicosanoid biosynthesis inhibitor, dexamethasone, strongly reduced nodulation responses to bacterial infections; 3) the influence of dexamethasone was reversed by injecting the eicosanoid-precursor polyunsaturated fatty acid, arachidonic acid (20:4n-6), into dexamethasone-treated, infected larvae; 4) the presence of an eicosanoid biosynthesis system in silkworms was documented. Demonstrated elements include a digestive phospholipase A2, incorporation of exogenous 20:4n-6 into fat body phospholipids, the presence of 20:4n-6 in cellular phospholipids, a fat body intracellular phospholipase A2 that can hydrolyze 20:4n-6 from cellular phospolipids, and eicosanoid biosynthetic enzymes; and 5) these findings support the hypothesis that eicosanoids mediate cellular immune responses to bacterial infections in silkworms.
Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems
Journal of Experimental Biology, 2005
Prostaglandins, together with thromboxanes (collectively termed prostanoids), are fatty acid derivatives of significant importance in many physiological processes. These compounds are formed following the action of cyclooxygenases (COX) and associated enzymes on C20 polyunsaturated fatty acid precursors released from phospholipids in membranes. Nearly all mammalian cell types have the biosynthetic machinery to produce at least one type of prostanoid. The same C20 fatty acid substrates can also be acted upon by lipoxygenases to produce mono-di-and trihydroxy derivatives such as leukotrienes, lipoxins and resolvins. The final route is the cytochrome P 450 pathway that can convert C20 fatty acids to hydroxylated derivatives.
International Immunology, 1996
Despite this immune suppression, responses indicative of T h 2 subset activation are present, including unusually high levels of specific lgG4. We tested the possibility that infection with filarial nematodes causes a reduction in the co-stimulatory or antigen-presenting capacity of macrophages resulting in a failure to activate specific T cells. Adherent peritoneal exudate cells (PEC) from mice implanted with adult B. malayi were used to present antigen to the conalbumin-specific T cell clone, D10.G4. Proliferation of the D10 cells at even background levels was completely blocked by the presence of implant-derived adherent PEC. However, cytokine production by these cells in response to antigen was intact, and thus PEC from implanted mice are capable of functionally processing and presenting antigen. The elicitation of a suppressive cell population was specific for live adults as cells from mice implanted with dead adult parasites effectively stimulated D10 proliferation. The block in cellular proliferation is not due to the production of factors typically associated with macrophage suppression such as nitric oxide, prostaglandins or catalase. These observations are consistent with the T cell hyporesponsiveness seen in human cases of patent Brugia infection and may provide a murine model for the immune suppression seen in lymphatic filariasis.
The FASEB Journal, 2016
Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L.