PLoS Pathog. 15, e1007597 (2019)

During microbial infection, inflammatory lipids such as eicosanoids are generated by host macrophages to kill invading pathogens. The fungus Cryptococcus neoformans produces eicosanoid species that are indistinguishable from their vertebrate counterparts, and an eicosanoid-deficient C. neoformans strain (Δplb1) has less robust growth and survival within host macrophages in vitro, suggesting that the fungus disrupts host eicosanoid signaling to promote its growth. In support of this model, Evans et al. found that addition of exogenous prostaglandin E2 (PGE2) could recover the intracellular proliferation of the Δplb1 mutant and enhance the virulence of this mutant in a zebrafish infection model. This activity required the dehydrogenated form of PGE2, 15-keto-prostaglandin E2. While knockout of the C. neoformans PGE2 biosynthetic enzyme limited C. neoformans growth in vitro or in vivo, inhibition and knockdown of host prostaglandin synthesis had no effect. The authors further found that the growth of C. neoformans during infection required activation of the host nuclear receptor PPAR-γ with 15-keto-PGE2 as the agonist. These results suggest that C. neoformans-derived PGE2 is converted to 15-keto-PGE2 to activate host PPAR-γ, thereby manipulating host immunity to promote its own growth.

Credit: PLoS