Methamphetamine Enhances Cryptococcus neoformans Melanization, Antifungal Resistance, and Pathogenesis in a Murine Model of Drug Administration and Systemic Infection.
Methamphetamine Enhances Cryptococcus neoformans Melanization, Antifungal Resistance, and Pathogenesis in a Murine Model of Drug Administration and Systemic Infection.
复制标题
甲基苯丙胺增强小鼠给药和全身感染模型中的新型隐球菌黑化、抗真菌耐药性和发病机制。
DOI：
10.1128/iai.00091-22
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发表时间：
2022
影响因子：
3.1
通讯作者：
Martinez,LuisR
中科院分区：
文献类型：
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作者：
Erives,VictorH;Munzen,MelissaE;Zamith-Miranda,Daniel;Hernandez,Hazael;Manepalli,Swetha;Nguyen,LongN;Hamed,MohamedF;Nosanchuk,JoshuaD;Martinez,LuisR
甲基苯丙胺 (METH) 是美国的一个主要公共卫生和安全问题。长期滥用冰毒会导致 HIV 感染风险增加 2 倍，并可能导致其他感染，尤其是通过呼吸道或皮肤进入的感染。新型隐球菌是一种有荚膜的机会性酵母样真菌，是免疫功能低下患者（尤其是艾滋病患者）脑膜脑炎的相对常见原因。新型隐球菌在哺乳动物感染过程中黑化，这一过程可能使用宿主提供的化合物，如儿茶酚胺。l-3,4-二羟基苯丙氨酸 (l-Dopa) 是一种天然儿茶酚胺，经常用于诱导新型隐球菌黑色化。l-多巴黑化隐球菌表现出对辐射、吞噬作用、去污剂和重金属的抵抗力。使用全身小鼠感染模型和体外测定来严格评估冰毒对新型隐球菌黑化和发病机制的影响，我们证明，感染黑化酵母细胞的冰毒治疗小鼠血液和大脑中的真菌负荷增加，从而加剧了死亡率。有趣的是，对暴露于冰毒的隐球菌培养物添加l-多巴的分析表明，冰毒会加速真菌黑化，这是一种适应外部刺激的事件，在发病过程中可能有利于真菌。我们的研究结果提供了新的证据，证明滥用冰毒对宿主体内平衡的影响以及对机会性微生物的宽容度增加。
Methamphetamine (METH) is a major public health and safety problem in the United States. Chronic METH abuse is associated with a 2-fold-higher risk of HIV infection and, possibly, additional infections, particularly those that enter through the respiratory tract or skin. Cryptococcus neoformans is an encapsulated opportunistic yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients, especially in individuals with AIDS. C. neoformans melanizes during mammalian infection in a process that presumably uses host-supplied compounds such as catecholamines.l-3,4-Dihydroxyphenylalanine (l-Dopa) is a natural catecholamine that is frequently used to induce melanization in C. neoformans.l-Dopa-melanized cryptococci manifest resistance to radiation, phagocytosis, detergents, and heavy metals. Using a systemic mouse model of infection andin vitroassays to critically assess the impact of METH on C. neoformans melanization and pathogenesis, we demonstrated that METH-treated mice infected with melanized yeast cells showed increased fungal burdens in the blood and brain, exacerbating mortality. Interestingly, analyses of cultures of METH-exposed cryptococci supplemented withl-Dopa revealed that METH accelerates fungal melanization, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.