Abstract
Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.
Highlights
IntroductionMacrophages must become activated by further inflammatory signals from the host immune system before they can effectively kill C. neoformans [3, 4]
Cryptococcus neoformans is an opportunistic pathogen that infects individuals who have severe immunodeficiencies such as late-stage HIV AIDS
Using a combination of in vitro and in vivo infection models we identify a specific eicosanoid species—prostaglandin E2 –that is required by C. neoformans for growth during infection
Summary
Macrophages must become activated by further inflammatory signals from the host immune system before they can effectively kill C. neoformans [3, 4]. Eicosanoids are an important group of lipid inflammatory mediators produced by innate immune cells such as macrophages. Macrophages produce large amounts of a particular group of eicosanoids called prostaglandins during microbial infection [10, 11]. Macrophages produce both PGE2 and PGD2 to which, via autocrine routes, they are highly responsive [12]. The synthesis of eicosanoids such as PGE2 is carefully regulated by feedback loops to ensure that the potent effects of these molecules are properly constrained. Exogenous sources of eicosanoids within the body, such as from eicosanoid-producing parasites [13] or tumours that overproduce eicosanoids [14, 15], can disrupt host inflammatory signaling as they are not subject to the same regulation
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