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

Research output: Contribution to journalArticle

Authors

  • Robert J Evans
  • Katherine Pline
  • Catherine A Loynes
  • Sarah Needs
  • Maceler Aldrovandi
  • Jens Tiefenbach
  • Rachel E Rubino
  • Christopher J Nicol
  • Henry M Krause
  • Valerie B O'Donnell
  • Stephen A Renshaw
  • Simon A Johnston

Colleges, School and Institutes

External organisations

  • Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, South Yorkshire, United Kingdom.
  • Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, West Midlands, United Kingdom.
  • Systems Immunity Research Institute, and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, South Glamorgan, United Kingdom.
  • InDanio Bioscience Inc., Toronto, Ontario, Canada.
  • Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.

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.

Details

Original languageEnglish
Pages (from-to)e1007597
Number of pages28
JournalPLoS pathogens
Volume15
Issue number3
Publication statusPublished - 28 Mar 2019