RT Journal Article
SR Electronic
T1 Fungal derived 15-keto-prostaglandin E<sub>2</sub> and host peroxisome proliferator-activated receptor gamma (PPAR-<em>γ</em>) promote <em>C. neoformans</em> growth during infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 113167
DO 10.1101/113167
A1 Robert J. Evans
A1 Sarah Needs
A1 Ewa Bielska
A1 Robin C. May
A1 Stephen A. Renshaw
A1 Simon A. Johnston
YR 2017
UL http://biorxiv.org/content/early/2017/03/06/113167.abstract
AB Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans can use 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 a key role for eicosanoid lipid mediators produced by C. neoformans in regulating host responses. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using the eicosanoid deficient cryptococcal mutant Δplb1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and, using our zebrafish model of cryptococcosis, we confirm this role for PGE2 in vivo. Furthermore, we show that PGE2 must be dehydrogenated into 15-keto PGE2 to promote fungal growth. We find that activation of the intracellular 15-keto PGE2 receptor PPAR-γ promotes fungal burden in zebrafish suggesting that cryptococcal 15-keto-PGE2 is a novel virulence factor that may act as an agonist for PPAR-γ.Author Summary Cryptococcus neoformans is an opportunistic fungal pathogen that is responsible for significant numbers of deaths in the immunocompromised population worldwide. Here we address whether eicosanoids produced by C. neoformans manipulate host innate immune cells during infection. Cryptococcus neoformans produces a number of eicosanoids that are notable for their similarity to vertebrate eicosanoids, it is therefore possible that fungal-derived eicosanoids may mimic physiological effects in the host. 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. We subsequently find that prostaglandin E2 must be converted to 15-keto prostaglandin E2 within the host before it has these effects. Furthermore, we provide evidence that the mechanism of prostaglandin E2/15-keto prostaglandin E2 mediated virulence is via activation of host PPAR-γ – an intracellular eicosanoid receptor known to interact with 15-keto PGE2.