SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway.
SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway.
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作者：
Bortolotti D;Gentili V;Rizzo S;Rotola A;Rizzo R
自然杀伤细胞在控制病毒感染方面很重要。然而，NK细胞在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染过程中的作用以前尚未确定。在SARS-CoV和SARS-CoV-2刺突蛋白存在的情况下，对来自SARS-CoV和SARS-CoV-2初治受试者的外周血NK细胞的活化、脱粒和干扰素-γ表达进行了评价。用刺突蛋白转染K562和肺上皮细胞，并与NK细胞共培养。通过流式细胞术和免疫荧光进行分析。在K562体外模型中，SARS-CoV和SARS-CoV-2刺突蛋白不改变NK细胞活化。相反，SARS-CoV-2 spike 1蛋白（SP1）在肺上皮细胞的细胞内表达导致NK细胞减少脱粒。进一步的实验揭示了肺上皮细胞表面上HLA-E表达的伴随诱导和SP1衍生的HLA-E结合肽的识别。同时，当肺上皮细胞中表达SP1时，NK细胞上的抑制性受体NKG 2A/CD 94的调节增加。我们排除了GATA 3转录因子作为负责HLA-E水平增加和HLA-E/NKG 2A相互作用涉及NK细胞耗竭的原因。我们首次表明NK细胞通过HLA-E/NKG 2A相互作用受到肺上皮细胞中SP1表达的影响。NK细胞的耗竭可能参与了SARS-CoV-2感染的免疫发病机制。
Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells’ exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.
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