The role of Candida albicans AP-1 protein against host derived ROS in in vivo models of infection
The role of Candida albicans AP-1 protein against host derived ROS in in vivo models of infection
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DOI：
10.4161/viru.22700
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发表时间：
2013-01-01
期刊：
影响因子：
5.2
通讯作者：
Rao, Reeta P.
中科院分区：
文献类型：
--
作者：
Jain, Charu;Pastor, Kelly;Rao, Reeta P.
白色念珠菌是人类的主要真菌病原体，可引起难以消除的粘膜感染和主要由于宿主先天状态缺陷而导致致命的全身感染。在这里，我们通过探索活性氧（ROS）作为对抗白色念珠菌感染的关键先天反应的作用，展示了秀丽隐杆线虫（一种研究先天免疫的模型宿主）的效用。与人类宿主非常相似，线虫的先天免疫反应被激活，产生活性氧以应对真菌感染。我们使用对 ROS 敏感的白色念珠菌 cap1 突变体作为工具来剖析这种生理性先天免疫反应，并表明 cap1 突变体不会引起疾病和死亡，但 bli-3 突变体蠕虫除外，因为 NADPH 氧化酶缺陷而无法产生 ROS。我们进一步验证了哺乳动物吞噬细胞中 ROS 介导的宿主防御机制，证明对培养的巨噬细胞中 NADPH 氧化酶的化学抑制使原本易受影响的 cap1 突变体能够抵抗 ROS 介导的吞噬作用。在播散性小鼠模型中，CAP1 的缺失导致毒力减弱最小，这表明 CAP1 独立机制有助于病原体在体内的存活。我们的研究结果强调了感染过程中的一个中心主题——白色念珠菌采用的毒力策略与宿主先天免疫系统之间的复杂平衡，并验证了秀丽隐杆线虫作为在分子水平上剖析这种平衡的简单模型宿主。
Candida albicans is a major fungal pathogen of humans, causing mucosal infections that are difficult to eliminate and systemic infections that are often lethal primarily due to defects in the host's innate status. Here we demonstrate the utility of Caenorhabditis elegans, a model host to study innate immunity, by exploring the role of reactive oxygen species (ROS) as a critical innate response against C. albicans infections. Much like a human host, the nematode's innate immune response is activated to produce ROS in response to fungal infection. We use the C. albicans cap1 mutant, which is susceptible to ROS, as a tool to dissect this physiological innate immune response and show that cap1 mutants fail to cause disease and death, except in bli-3 mutant worms that are unable to produce ROS because of a defective NADPH oxidase. We further validate the ROS-mediated host defense mechanism in mammalian phagocytes by demonstrating that chemical inhibition of the NADPH oxidase in cultured macrophages enables the otherwise susceptible cap1 mutant to resists ROS-mediated phagolysis. Loss of CAP1 confers minimal attenuation of virulence in a disseminated mouse model, suggesting that CAP1-independent mechanisms contribute to pathogen survival in vivo. Our findings underscore a central theme in the process of infection-the intricate balance between the virulence strategies employed by C. albicans and the host's innate immune system and validates C. elegans as a simple model host to dissect this balance at the molecular level.