Cell surface nucleotide-metabolizing enzyme, ectonucleotidase-CD73, has emerged as a central component of the cellular homeostatic-machinery that counterbalances the danger-molecule (extracellular-ATP)-driven proinflammatory response in immune cells. While the importance of CD73 in microbial host fitness and symbiosis is gradually being unraveled, there remains a significant gap in knowledge of CD73 and its putative role in epithelial cells. Here, we depict a novel host-pathogen adaptation mechanism where CD73 takes a center role in the intracellular persistence of Porphyromonas gingivalis, a major colonizer of oral mucosa, using human primary gingival epithelial cell (GEC) system. Temporal analyses revealed, upon invasion into the GECs, P. gingivalis can significantly elevate the host-surface CD73 activity and expression. The enhanced and active CD73 significantly increases P. gingivalis intracellular growth in the presence of substrate-AMP and simultaneously acts as a negative regulator of reactive oxygen species (ROS) generation upon eATP treatment. The inhibition of CD73 by siRNA or by a specific inhibitor markedly increases ROS production. Moreover, CD73 and P. gingivalis cross-signaling significantly modulates pro-inflammatory interleukin-6 (IL-6) in the GECs. Conversely, exogenous treatment of the infected GECs with IL-6 suppresses the intracellular bacteria via amplified ROS generation. However, the decreased bacterial levels can be restored by overexpressing functionally active CD73. Together, these findings illuminate how the local extracellular-purine-metabolism, in which CD73 serves as a core molecular switch, can alter intracellular microbial colonization resistance. Further, host-adaptive pathogens such as P. gingivalis can target host ectonucleotidases to disarm specific innate defenses for successful intracellular persistence in mucosal epithelia.

中文翻译：

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宿主表面胞外核苷酸酶CD73和机会病原体牙龈卟啉单胞菌的交叉调节为人类上皮细胞中慢性细菌存活提供了新的体内平衡机制。

细胞表面核苷酸代谢酶，外切核苷酸酶CD73，已成为细胞体内平衡机制的重要组成部分，该机制平衡了免疫细胞中危险分子（细胞外ATP）驱动的促炎反应。尽管CD73在微生物宿主适应和共生中的重要性正在逐步被阐明，但是CD73及其在上皮细胞中的假定作用的知识仍然存在巨大差距。在这里，我们描述了一种新型的宿主-病原体适应机制，其中CD73在使用人原发性牙龈上皮细胞（GEC）系统的牙龈卟啉单胞菌（口腔黏膜的主要定居者）的细胞内持久性中起着中心作用。时间分析显示，侵袭GECs后，牙龈卟啉单胞菌可以显着提高宿主表面CD73的活性和表达。在底物-AMP存在下，增强的活性CD73显着增加了牙龈卟啉单胞菌的细胞内生长，并同时充当eATP处理后产生的活性氧（ROS）的负调节剂。siRNA或特异性抑制剂对CD73的抑制作用显着增加了ROS的产生。此外，CD73和牙龈卟啉单胞菌交叉信号显着调节GEC中的促炎性白介素6（IL-6）。相反，用IL-6对感染的GEC进行外源处理可通过放大的ROS生成抑制细胞内细菌。但是，降低的细菌水平可以通过过表达功能活性CD73来恢复。这些发现共同阐明了CD73充当核心分子开关的局部细胞外嘌呤代谢，可以改变细胞内微生物的定植抗性。此外，宿主适应性病原体（例如牙龈卟啉单胞菌）可以靶向宿主胞外核苷酸酶来解除特定的先天防御，从而在粘膜上皮细胞中成功实现细胞内持久性。