隐球菌病,由隐球菌属真菌引起的,表现在广泛的临床表现中,包括严重的肺炎和中枢神经系统(CNS)和其他组织(骨骼和皮肤)的疾病。免疫缺陷或过度炎症反应的发展可导致易感性增加或宿主损伤。分别,在真菌接触期间。白三烯有助于调节针对真菌感染的炎症反应。然而,研究表明,隐球菌利用宿主5-脂氧合酶(5-LO),花生四烯酸代谢为白三烯的中心酶,促进跨脑血屏障的迁移。探讨宿主5-LO对隐球菌病中保护性宿主免疫反应和死亡率的影响。给予野生型(C57BL/6)和5-脂氧合酶缺陷(5-LO-/-)小鼠实验性肺部和全身性隐球菌。,感染。我们的结果表明,5-LO-/-小鼠表现出减少的病理和更好的疾病结果(即,没有与隐球菌性脑膜脑炎相关的死亡或体征),尽管脑组织中有可检测的酵母。相比之下,C57BL/6小鼠表现出与隐球菌性脑膜脑炎相关的经典体征。此外,5-LO-/-小鼠的脑组织表现出与隐球菌相关的免疫重建炎症综合征(C-IRIS)临床相关的较低水平的细胞因子(CCL2和CCL3)。在隐球菌病的系统性小鼠模型中,5-LO-/-小鼠和用联邦药物管理局(FDA)批准的5-LO合成抑制剂治疗的小鼠,齐留顿,与C57BL/6感染的小鼠相比,死亡率显着降低。这些结果表明,旨在抑制宿主5-LO信号传导的疗法可以降低与隐球菌性脑膜脑炎相关的疾病病理和死亡率。
目的:隐球菌病是一种全球分布的真菌病,临床表现广泛,包括中枢神经系统的疾病。全球范围内,估计有179,000例隐球菌性脑膜炎,每年约有112,000人死亡,占与艾滋病有关的死亡人数的19%。了解在隐球菌病中宿主免疫反应是如何调节的,对于减轻与隐球菌病相关的发病率和死亡率至关重要。已显示白三烯(LTs)在感染期间调节炎症反应。在这项研究中,我们显示缺乏5-脂氧合酶(5-LO)的小鼠,花生四烯酸代谢为白三烯的中心酶,表现出减少的病理,疾病,以及与隐球菌性脑膜炎相关的神经系统症状.此外,接受实验性隐球菌感染并随后接受FDA批准的5-LO合成抑制剂治疗的小鼠的死亡率显着降低.这些结果表明,旨在抑制宿主5-LO活性的疗法可以显着降低与隐球菌性脑膜炎相关的病理和死亡率。
Cryptococcosis, caused by fungi of the genus Cryptococcus, manifests in a broad range of clinical presentations, including severe pneumonia and disease of the central nervous system (CNS) and other tissues (bone and skin). Immune deficiency or development of overexuberant inflammatory responses can result in increased susceptibility or host damage, respectively, during fungal encounters. Leukotrienes help regulate inflammatory responses against fungal infections. Nevertheless, studies showed that Cryptococcus exploits host 5-lipoxygenase (5-LO), an enzyme central to the metabolism of arachidonic acid into leukotrienes, to facilitate transmigration across the brain-blood barrier. To investigate the impact of host 5-LO on the development of protective host immune responses and mortality during cryptococcosis, wild-type (C57BL/6) and 5-lipoxygenase-deficient (5-LO-/-) mice were given experimental pulmonary and systemic Cryptococcus sp., infections. Our results showed that 5-LO-/- mice exhibited reduced pathology and better disease outcomes (i.e., no mortality or signs associated with cryptococcal meningoencephalitis) following pulmonary infection with C. deneoformans, despite having detectable yeast in the brain tissues. In contrast, C57BL/6 mice exhibited classical signs associated with cryptococcal meningoencephalitis. Additionally, brain tissues of 5-LO-/- mice exhibited lower levels of cytokines (CCL2 and CCL3) clinically associated with Cryptococcus-related immune reconstitution inflammatory syndrome (C-IRIS). In a systemic mouse model of cryptococcosis, 5-LO-/- mice and those treated with a Federal Drug Administration (FDA)-approved 5-LO synthesis inhibitor, zileuton, displayed significantly reduced mortality compared to C57BL/6 infected mice. These results suggest that therapeutics designed to inhibit host 5-LO signaling could reduce disease pathology and mortality associated with cryptococcal meningoencephalitis.
OBJECTIVE: Cryptococcosis is a mycosis with worldwide distribution and has a broad range of clinical manifestations, including diseases of the CNS. Globally, there is an estimated 179,000 cases of cryptococcal meningitis, resulting in approximately 112,000 fatalities per annum and 19% of AIDS-related deaths. Understanding how host immune responses are modulated during cryptococcosis is central to mitigating the morbidity and mortality associated with cryptococcosis. Leukotrienes (LTs) have been shown to modulate inflammatory responses during infection. In this study, we show that mice deficient in 5-lipoxygenase (5-LO), an enzyme central to the metabolism of arachidonic acid into leukotrienes, exhibit reduced pathology, disease, and neurological signs associated with cryptococcal meningitis. Additionally, mice given an experimental cryptococcal infection and subsequently treated with an FDA-approved 5-LO synthesis inhibitor exhibited significantly reduced mortality rates. These results suggest that therapeutics designed to inhibit host 5-LO activity could significantly reduce pathology and mortality rates associated with cryptococcal meningitis.