PDF(Pubmed)
Abstract：
UNASSIGNED: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s).
UNASSIGNED: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs.
UNASSIGNED: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals.
UNASSIGNED: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects.
UNASSIGNED: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs.
UNASSIGNED: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals.
UNASSIGNED: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects.
摘要：
■在2019年早期感染或严重冠状病毒病（COVID-19）患者中，循环NK细胞持续减少，尽管被高度激活或筋疲力尽。本文的目的是确定严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突糖蛋白（SP）是否可以直接触发NK细胞并通过其受体。
■已经评估了SP刺激的人类NK细胞的活化标志物的表达，细胞因子释放，和细胞毒活性，以及基因表达谱和NF-kB磷酸化，它们已经被特定的小干扰RNA沉默了。
■来自武汉菌株的SP和其他关注变体（VOCs）通过增加激活标记表达直接结合并刺激纯化的NK细胞，细胞因子释放，和细胞溶解活性，主要存在于CD56brightNK细胞亚群中。VOC-SP在激活NK细胞的能力上有所不同，G614和Delta-Plus菌株在大多数供体中提供最强的活性。虽然VOC-SP不触发ACE2，其在NK细胞上不表达，或其他激活受体，它们直接和可变地结合Toll样受体2(TLR2)和TLR4。此外，SP驱动的NK细胞功能在掩蔽此类受体或沉默相关基因时被抑制。最后,在回收的COVID-19中，VOC-SP上调CD56dimNK细胞功能，但不是在非感染者中，个人。
■TLR2和TLR4是NK细胞中SP的新型激活受体，提示这些细胞在协调SARS-CoV-2感染的病理生理学中的新作用。这一发现的致病相关性突出了这一事实，即在SARS-CoV-2发炎的环境以及感染和长期COVID-19受试者的血浆中经常检测到提供NK细胞活化的游离SP。
■已经评估了SP刺激的人类NK细胞的活化标志物的表达，细胞因子释放，和细胞毒活性，以及基因表达谱和NF-kB磷酸化，它们已经被特定的小干扰RNA沉默了。
■来自武汉菌株的SP和其他关注变体（VOCs）通过增加激活标记表达直接结合并刺激纯化的NK细胞，细胞因子释放，和细胞溶解活性，主要存在于CD56brightNK细胞亚群中。VOC-SP在激活NK细胞的能力上有所不同，G614和Delta-Plus菌株在大多数供体中提供最强的活性。虽然VOC-SP不触发ACE2，其在NK细胞上不表达，或其他激活受体，它们直接和可变地结合Toll样受体2(TLR2)和TLR4。此外，SP驱动的NK细胞功能在掩蔽此类受体或沉默相关基因时被抑制。最后,在回收的COVID-19中，VOC-SP上调CD56dimNK细胞功能，但不是在非感染者中，个人。
■TLR2和TLR4是NK细胞中SP的新型激活受体，提示这些细胞在协调SARS-CoV-2感染的病理生理学中的新作用。这一发现的致病相关性突出了这一事实，即在SARS-CoV-2发炎的环境以及感染和长期COVID-19受试者的血浆中经常检测到提供NK细胞活化的游离SP。
