Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain.
Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain.
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DOI：
10.1111/cmi.12661
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发表时间：
2017-03
影响因子：
3.4
通讯作者：
Kim KS
中科院分区：
文献类型：
--
作者：
Zhu L;Maruvada R;Sapirstein A;Peters-Golden M;Kim KS
中枢神经系统（CNS）的新型隐球菌感染仍然是死亡和发病的重要原因，其中一个主要因素是我们对这种疾病发病机制的不完全了解。在这里，我们提供了第一个直接证据，表明新型隐球菌利用宿主半胱氨酰白三烯（LT）穿透血脑屏障，LTs是通过涉及胞质磷脂酶A2α（cPLA2α）和5-脂氧合酶（5-LO）的LT生物合成途径形成的，并通过1型半胱氨酰白三烯受体（CysLT1）发挥作用。 cPLA2α和5-LO的基因缺失以及cPLA2α、5-LO和CysLT1的药理抑制可有效阻止新型隐球菌在体外和体内渗透血脑屏障。 CysLT1 拮抗剂增强了抗真菌药物治疗小鼠新型隐球菌中枢神经系统感染的功效。这些发现表明，宿主半胱氨酰LT依赖于cPLA2α和5-LO的作用，促进新型隐球菌穿透血脑屏障，并代表了阐明新型隐球菌CNS感染的发病机制和治疗开发的新靶标。
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 as well as 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.