Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host
Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host
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DOI：
10.1086/599328
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发表时间：
2009-07-01
影响因子：
6.4
通讯作者：
Nosanchuk, Joshua D.
中科院分区：
文献类型：
--
作者：
Martinez, Luis R.;Mihu, Mircea Radu;Nosanchuk, Joshua D.
甲基苯丙胺对宿主对机会性病原体反应的影响尚未得到广泛的描述。甲基苯丙胺是美国一个主要的公共健康和安全问题。慢性甲基苯丙胺滥用与人类免疫缺陷病毒感染风险增加2倍有关，并可能导致其他感染。荚膜组织原体是一种二形真菌，在美国中西部地区流行，可引起呼吸道和全身疾病，特别是在免疫力受损的个体中。我们发现甲基苯丙胺破坏了正常的巨噬细胞功能，导致无法控制组织胞浆菌病。甲基苯丙胺通过碱化吞噬体降低原代巨噬细胞对酵母的吞噬作用和杀伤作用。此外，在感染荚膜囊胞杆菌之前接受甲基苯丙胺的小鼠免疫功能受损，真菌负担增加，肺部炎症增加，存活率降低。甲基苯丙胺的免疫抑制可能与感染小鼠肺部细胞因子的失调、巨噬细胞内荚膜囊胞杆菌的异常加工以及巨噬细胞表面参与吞噬的MAC-1受体的固定化有关。此外，甲基苯丙胺抑制T细胞增殖并改变抗体产生，这是适应性免疫的重要组成部分。利用小鼠组织胞浆菌病模型，本研究确定甲基苯丙胺可能改变宿主的免疫系统并增强真菌的发病机制。
The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-1 receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.