Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes

Abstract

Oxylipins are oxygenated metabolites of fatty acids. Eicosanoids are a subset of oxylipins and include the prostaglandins and leukotrienes, which are potent regulators of host immune responses. Host cells are one source of eicosanoids and oxylipins during infection; however, another potential source of eicosanoids is the pathogen itself. A broad range of pathogenic fungi, protozoa, and helminths produce eicosanoids and other oxylipins by novel synthesis pathways. Why do these organisms produce oxylipins? Accumulating data suggest that phase change and differentiation in these organisms are controlled by oxylipins, including prostaglandins and lipoxygenase products. The precise role of pathogen-derived eicosanoids in pathogenesis remains to be determined, but the potential link between pathogen eicosanoids and the development of TH2 responses in the host is intriguing. Mammalian prostaglandins and leukotrienes have been studied extensively, and these molecules can modulate Th1 versus Th2 immune responses, chemokine production, phagocytosis, lymphocyte proliferation, and leukocyte chemotaxis. Thus, eicosanoids and oxylipins (host or microbe) may be mediators of a direct host-pathogen "cross-talk" that promotes chronic infection and hypersensitivity disease, common features of infection by eukaryotic pathogens.

FIG. 1.

Chemical structures of the 18- and 20-carbon fatty acid molecules that serve as the precursors for eicosanoid and oxylipin synthesis.

FIG. 2.

Synthesis of 1, 2, and 3 series prostaglandins: different C₂₀ fatty acids are used as precursors for the 1, 2, and 3 series prostaglandins (e.g., PGE₁, PGE₂, and PGE₃). The series number corresponds to the number of double bonds in the fatty acid side chains of the prostaglandin.

FIG. 3.

Pathways to prostaglandin and leukotriene synthesis from arachidonic acid. Cysteinyl leukotrienes include LTC₄, LTD₄, and LTE₄.

FIG. 4.

Mechanism of cyclooxygenase action. The formation of PGH₂ is a two-step process beginning with the addition of two dioxygen molecules to arachidonic acid, followed by reduction of the peroxide at C-15.

FIG. 5.

Jasmonic acid synthesis. The jasmonic acid cascade is utilized by plants and represents an alternative method for the formation of prostanoid-like molecules without a cyclooxygenase. 13-HpOTE, 13-hydroperoxyoctadecatrienoic acid.

FIG. 6.

Mechanism of lipoxygenase action. The first hydrogen abstraction takes place from a doubly allylic methylene (a CH₂ group flanked on either side by -CH=CH-), followed by the attack of a dioxygen molecule at C-2 from the radical and subsequent bond rearrangement.

FIG. 7.

Other fungal lipid signaling molecules. (a) trans,trans stereoisomer of farnesol (C₁₅H₂₆O₅), a quorum-sensing molecule in Candida albicans. (b and c) Diacylated urea compounds isolated from Saccharomyces cerevisiae that have recently been identified as chemoattractant molecules.

FIG. 8.

Formation of lipoxins by lipoxygenases. Lipoxin A₄ is another eicosanoid derivative of lipoxygenases that has recently been implicated in the immune response to Toxoplasma gondii. 5-LOX, 5-lipoxygenase; 12-LOX, 12-lipoxygenase; 15-LOX, 15-lipoxygenase; HpETE, hydroperoxyeicosatetraenoic acid.