Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain |
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| Authors: | Longkun Zhu Ravi Maruvada Adam Sapirstein Marc Peters‐Golden Kwang Sik Kim |
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| Institution: | 1. Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Department of Cell Biology and Medical Genetics/Center for Cell and Developmental Biology, School of Basic Medical Sciences Fujian Medical University, Fuzhou, Fujian, China;3. Department of Anesthesiology and Critical Care Medicine, Baltimore, MD, USA;4. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA |
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| 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. |
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