Open AccessCysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain
Author(s) -
Zhu Longkun,
Maruvada Ravi,
Sapirstein Adam,
PetersGolden Marc,
Kim Kwang Sik
Publication year - 2017
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12661
Subject(s) - cryptococcus neoformans , biology , blood–brain barrier , cryptococcosis , pathogenesis , in vivo , immunology , microbiology and biotechnology , penetration (warfare) , leukotriene , central nervous system , neuroscience , genetics , asthma , operations research , engineering
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 A 2 α (cPLA 2 α) and 5‐lipoxygenase (5‐LO) and acting via cysteinyl leukotriene type 1 receptor (CysLT1), for penetration of the blood–brain barrier. Gene deletion of cPLA 2 α and 5‐LO and pharmacological inhibition of cPLA 2 α, 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 cPLA 2 α 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.