Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain

Longkun Zhu, Ravi Maruvada, Adam Sapirstein, Marc Peters-Golden, Kwang Sik Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Cryptococcus neoformas infection of the central nervous system (CNS) continues to be an important cause of mortality and morbidity, and a major contributing factor is our incomplete knowledge of the pathogenesis of this disease. Here, we provide the first direct evidence that C. neoformans exploits host cysteinyl leukotrienes (LTs), formed via LT biosynthetic pathways involving cytosolic phospholipase A2α (cPLA2α) and 5-lipoxygenase (5-LO) and acting via cysteinyl leukotriene type 1 receptor (CysLT1), for penetration of the blood–brain barrier. Gene deletion of cPLA2α and 5-LO and pharmacological inhibition of cPLA2α, 5-LO and CysLT1 were effective in preventing C. neoformans penetration of the blood–brain barrier in vitro and in vivo. A CysLT1 antagonist enhanced the efficacy of an anti-fungal agent in therapy of C. neoformans CNS infection in mice. These findings demonstrate that host cysteinyl LTs, dependent on the actions of cPLA2α and 5-LO, promote C. neoformans penetration of the blood–brain barrier and represent novel targets for elucidating the pathogenesis and therapeutic development of C. neoformans CNS infection.

Original languageEnglish (US)
Article numbere12661
JournalCellular microbiology
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

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