Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence.
Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence.
复制标题
在低氧气环境中逃避免疫监测会增强白色念珠菌的毒力。
DOI：
10.1128/mbio.02120-18
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发表时间：
2018-11-06
期刊：
影响因子：
6.4
通讯作者：
Urban CF
中科院分区：
文献类型：
--
作者：
Lopes JP;Stylianou M;Backman E;Holmberg S;Jass J;Claesson R;Urban CF
成功的人类殖民者已经进化出了绕过免疫监视的机制。 PMN 渗透到感染部位导致低氧生态位的产生。暴露于低氧水平会诱导真菌细胞壁掩蔽，进而阻碍中性粒细胞的病原体感应和抗真菌反应。通过增加缺氧条件下中性粒细胞代谢产生的乳酸量来延长细胞壁掩蔽效应。在无脊椎动物感染模型中，白色念珠菌能够在低氧条件下 2 天内杀死受感染的秀丽隐杆线虫线虫，而大多数未感染的对照线虫和受感染的线虫在含氧量正常的条件下存活下来。这些结果表明白色念珠菌受益于低氧生态位以增加毒力。在这些条件下，白色念珠菌与先天免疫细胞的相互作用促成了感染的总体结果。此外，适应低氧水平还可以降低对选定抗真菌药物的敏感性，从而对白色念珠菌有益。因此，低氧条件下宿主细胞的免疫调节可以为改善当前的抗真菌疗法提供有价值的方法。人类的微生物殖民者已经进化到能够适应环境线索并感知营养的可用性。氧气是不同宿主组织和不同类型感染中不断变化的环境参数。我们描述了白色念珠菌（一种机会性真菌病原体）如何在缺氧和缺氧下调节宿主反应。我们发现，多形核白细胞（PMN）对感染部位的高度浸润导致小鼠皮下脓肿中的低氧环境。持续的缺氧环境不会影响中性粒细胞的活力或代谢。然而，在缺氧情况下，白色念珠菌感染会扰乱特定的中性粒细胞反应。 PMN 无法有效吞噬、产生 ROS 或释放细胞外 DNA 陷阱。未能启动足够的反应是由于暴露于低氧水平时白色念珠菌细胞壁对 β-葡聚糖的掩蔽，这阻碍了 PMN 表面 Dectin-1 对 PAMP 的感应。这反过来又促进了免疫逃避并增强了真菌的存活率。在低氧条件下，PMN 产生的乳酸积累会延长细胞壁掩蔽效应。最后，对缺氧的适应增加了白色念珠菌的毒力，我们使用秀丽隐杆线虫感染模型证明了这一点。
Successful human colonizers have evolved mechanisms to bypass immune surveillance. Infiltration of PMNs to the site of infection led to the generation of a low oxygen niche. Exposure to low oxygen levels induced fungal cell wall masking, which in turn hindered pathogen sensing and antifungal responses by PMNs. The cell wall masking effect was prolonged by increasing lactate amounts produced by neutrophil metabolism under oxygen deprivation. In an invertebrate infection model, C. albicans was able to kill infected C. elegans nematodes within 2 days under low oxygen conditions, whereas the majority of uninfected controls and infected worms under normoxic conditions survived. These results suggest that C. albicans benefited from low oxygen niches to increase virulence. The interplay of C. albicans with innate immune cells under these conditions contributed to the overall outcome of infection. Adaption to low oxygen levels was in addition beneficial for C. albicans by reducing susceptibility to selected antifungal drugs. Hence, immunomodulation of host cells under low oxygen conditions could provide a valuable approach to improve current antifungal therapies. Microbial colonizers of humans have evolved to adapt to environmental cues and to sense nutrient availability. Oxygen is a constantly changing environmental parameter in different host tissues and in different types of infection. We describe how Candida albicans, an opportunistic fungal pathogen, can modulate the host response under hypoxia and anoxia. We found that high infiltration of polymorphonuclear leukocytes (PMNs) to the site of infection contributes to a low oxygen milieu in a murine subdermal abscess. A persistent hypoxic environment did not affect viability or metabolism of PMNs. Under oxygen deprivation, however, infection with C. albicans disturbed specific PMN responses. PMNs were not able to efficiently phagocytose, produce ROS, or release extracellular DNA traps. Failure to launch an adequate response was caused by C. albicans cell wall masking of β-glucan upon exposure to low oxygen levels which hindered PAMP sensing by Dectin-1 on the surfaces of PMNs. This in turn contributed to immune evasion and enhanced fungal survival. The cell wall masking effect is prolonged by the accumulation of lactate produced by PMNs under low oxygen conditions. Finally, adaptation to oxygen deprivation increased virulence of C. albicans which we demonstrated using a Caenorhabditis elegans infection model.