SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies.
SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies.
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DOI：
10.7554/elife.74489
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发表时间：
2022-05-19
期刊：
影响因子：
7.7
通讯作者：
Stanton, Richard J.
中科院分区：
文献类型：
--
作者：
Fielding, Ceri Alan;Sabberwal, Pragati;Williamson, James C.;Greenwood, Edward J. D.;Crozier, Thomas W. M.;Zelek, Wioleta;Seow, Jeffrey;Graham, Carl;Huettner, Isabella;Edgeworth, Jonathan D.;Price, David A.;Morgan, Paul B.;Ladell, Kristin;Eberl, Matthias;Humphreys, Ian R.;Merrick, Blair;Doores, Katie;Wilson, Sam J.;Lehner, Paul J.;Wang, Eddie C. Y.;Stanton, Richard J.
感染的结果取决于病毒操纵受感染细胞逃避免疫的能力，以及免疫应答克服这种逃避的能力。理解这一过程是理解发病机制、遗传风险因素以及自然和疫苗诱导免疫的关键。SARS-CoV-2拮抗先天性干扰素反应，但它是否操纵先天性细胞免疫尚不清楚。无偏蛋白质组学分析确定了SARS-CoV-2感染的肺上皮细胞上细胞表面蛋白质表达如何改变，显示了活化NK配体B7-H6、云母、ULBP 2和Nectin 1的下调，对MHC-I的影响最小。这发生在蛋白质合成水平，可以通过Nsp 1和Nsp 14介导，并与NK细胞活化的减少相关。这确定了SARS-CoV-2宿主关闭拮抗先天免疫的新机制。在疾病过程的后期，产生了强烈的抗体依赖性NK细胞激活（ADNKA）。这些反应在大多数患者中持续至少6个月，并导致高水平的促炎细胞因子产生。刺突特异性抗体的消耗证实了它们在中和中的主导作用，但与针对其他蛋白质（包括ORF 3a、膜和核衣壳）的抗体相比，这些抗体在ADNKA中仅起次要作用。相比之下，疫苗接种后诱导的ADNKA仅集中于尖峰，弱于自然感染后的ADNKA，并且第二剂未加强。这些见解对于理解疾病进展、疫苗有效性和疫苗设计具有重要意义。
The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.