Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.
Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.
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DOI：
10.1371/journal.ppat.1010941
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发表时间：
2023-04
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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被包裹的真菌新型隐球菌是真菌性脑膜炎最常见的病因，在艾滋病或免疫抑制患者中发病率最高。这种微生物通过吸入感染性颗粒进入人体。C.主要成分为葡糖醛酸甘露聚糖（GXM）的新型荚膜多糖在组织中广泛积累并损害宿主免疫应答。C.新生儿从肺进入血流，并通过转胞吞作用、旁胞吞作用或使用“特洛伊木马”机制进入吞噬细胞内部而进入脑。这种真菌会导致危及生命的脑膜脑炎，死亡率很高。因此，我们研究了鼻内给予外源性GXM对C。C57 BL/6小鼠中的新形虫感染。GXM增强隐球菌肺部感染，并促进真菌全身传播和脑侵袭。GXM的预攻击导致在肺、血清和令人惊讶的脑中检测到多糖，后者可能通过鼻腔到达。GXM在体内显著改变内皮细胞紧密连接蛋白的表达，提示对C。脑入侵的机制。使用微量滴定transwell系统，我们发现GXM破坏跨内皮电阻，削弱与周细胞共培养的人脑内皮细胞单层，周细胞是血脑屏障（BBB）中发现的血管/毛细血管的支持细胞，以促进C。新生儿血脑屏障渗透。我们的研究结果应该被认为是在治疗的发展，以打击隐球菌病的破坏性并发症，估计在全球范围内每年约20万人死亡。新型隐球菌感染的中枢神经系统（CNS）通常开始吸入真菌孢子，并导致毁灭性的死亡率在世界范围内。每年报告的死亡人数超过20万，其中隐球菌脑膜脑炎是最严重的疾病形式。本研究通过真菌多糖胶囊的特性研究了真菌入侵、定殖和对宿主造成损害的能力，真菌多糖胶囊允许微生物具有各种保护和攻击能力。这种胶囊主要由多糖葡糖醛酸甘露聚糖（GXM）制成，与CNS隐球菌感染的进展和严重程度有关。我们确定GXM增加了小鼠肺部的真菌负担，并增强了真菌向大脑的迁移。GXM与血脑屏障（一种调节颗粒进入CNS的保护性结构）的相互作用表明，GXM可以破坏该屏障的完整性，损害液体、免疫细胞和其他对维持CNS至关重要的因素的微妙平衡。本研究结果揭示了GXM在建立C.因此，需要进一步研究以进一步了解这些相互作用。
The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a “Trojan horse” mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year. Cryptococcus neoformans infection of the central nervous system (CNS) typically begins by inhalation of fungal spores and results in devastating mortality rates worldwide. Over 200,000 deaths have been reported annually, with cryptococcal meningoencephalitis being the most severe form of the disease. This study investigates the ability of the fungus to invade, colonize, and cause damage to the host through properties of the fungal polysaccharide capsule, which allows the microbe a variety of both protective and offensive abilities. This capsule, made primarily of the polysaccharide glucuronoxylomannan (GXM), has been implicated in the progression and severity of cryptococcal infection in the CNS. We determined that GXM increases the fungal burden in the lungs of mice and enhances fungal migration to the brain. Interaction of GXM with the blood-brain barrier, which is a protective structure that regulates movement of particles into the CNS, demonstrated that GXM can disrupt the integrity of this barrier, compromising the delicate balances of fluids, immune cells, and other factors vital to the maintenance of the CNS. The findings of this study reveal the substantial role of GXM in establishing C. neoformans infection in the brain and necessitate future studies to further understand these interactions.
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影响因子：
3.7
作者：
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