15-keto-prostaglandin E₂ activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection

Evans, Robert J, Pline, Katherine, Loynes, Catherine A., Needs, Sarah, Aldrovandi, Maceler, Tiefenback, Jens, Bielska, Ewa, Rubino, Rachel E., Nicol, Christopher J., May, Robin C., Krause, Henry M., O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460, Renshaw, Stephen A. and Johnstone, Simon A. 2019. 15-keto-prostaglandin E₂ activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection. PLoS Pathogens 15 (3) , e1007597. 10.1371/journal.ppat.1007597

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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-

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Public Library of Science
ISSN:	1553-7366
Date of First Compliant Deposit:	4 March 2019
Date of Acceptance:	25 January 2019
Last Modified:	05 May 2023 20:05
URI:	https://orca.cardiff.ac.uk/id/eprint/120121

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