The role of adaptive NK cells in the control of SARS-CoV-2 infection

适应性 NK 细胞在控制 SARS-CoV-2 感染中的作用

• 批准号: 458683039
• 负责人: Professor Dr. Markus G. Uhrberg
• 金额: --
• 依托单位: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/458683039?language=en
• 关键词: role; adaptive; NK; cells; control

Natural killer (NK) cells are part of the first line of defense against acute viral infections. Recently, a novel type of virus-specific adaptive NK cell was identified that expands during acute cytomegalovirus (CMV) infection and is generally hypersensitive to stimulation by IgG antibodies leading to highly efficient and rapid antibody-mediated cellular cytotoxicity (ADCC). A hallmark of these adaptive (also known as memory) NK cells is the expression of the stimulatory receptor NKG2C, which is specific for the Human Leucocyte Antigen E (HLA-E). We have recently shown that adaptive NKG2C+ NK cells are stably maintained as large clonal expansions in 30-40% of HCMV+ cases. Furthermore, we have shown that the size of these expansions correlates with the coexpression of KIR2DL receptors, which are inhibitory receptors for HLA-C and members of the highly polymorphic KIR family. Due to their high ADCC potential, adaptive NK cells could play a critical role in SARS-CoV-2 infection, which is often associated with strong IgG antibody responses. Indeed, it was recently shown that patients with severe disease exhibited increased presence of adaptive NK cells in the circulation. Importantly, in contrast to conventional NK cells, adaptive NK cells can persist for many years and thus have the potential to contribute to long-term protection against re-infection. In this project, we would like to find out how adaptive NKG2C+ NK cells influence the outcome of SARS-CoV-2 infection. We will address this in samples from convalescent COVID-19 patients (MU) as well as in a primate model of Covid-19 (LW). The Düsseldorf team has already collected samples and clinical data on >130 SARS-CoV-2 cases and would like to correlate the relevant clinical parameters such as disease severity, virus load, SARS-CoV-2-specific IgM and IgG titer, and CMV status with the presence of adaptive NK cells by multicolor flow cytometry. Furthermore, based on the recent observation that the SARS-CoV-2 spike protein SP1 leads to upregulation of HLA-E in lung epithelial cells, we will explore in vitro if this mechanism leads to stimulation and expansion of adaptive NK cells via the HLA-E/NKG2C axis. The Göttingen team at the German Primate Center (DPZ) could already demonstrate the presence of similar CMV-associated expansions in macaques on the basis of newly-developed mAbs specific for macaque NKG2C and KIR. We would thus like to study the contribution of adaptive NK cells in the acute phase of SARS-CoV-2 infection, employing experimentally infected rhesus macaques. The analysis of blood samples as well as tissue sections will give us the unique opportunity to monitor the distribution and functional role of adaptive NK cells in this primate model. If adaptive NK cells are indeed involved in control of SARS-CoV-2 infection, this innate immune cell type, which can be easily expanded in vitro, could provide a highly interesting novel option for allogeneic cellular therapy of COVID-19 patients.

自然杀伤 (NK) 细胞是抵抗急性病毒感染的第一道防线的一部分。最近，人们发现了一种新型病毒特异性适应性 NK 细胞，它在急性巨细胞病毒 (CMV) 感染期间会扩增，并且通常对 IgG 抗体的刺激高度敏感，从而导致高效、快速的抗体介导的细胞毒性 (ADCC)。这些适应性（也称为记忆）NK 细胞的一个标志是表达刺激性受体 NKG2C，该受体对人类白细胞抗原 E (HLA-E) 具有特异性。我们最近发现，在 30-40% 的 HCMV+ 病例中，适应性 NKG2C+ NK 细胞能够稳定维持大规模克隆扩增。此外，我们还表明，这些扩展的大小与 KIR2DL 受体的共表达相关，KIR2DL 受体是 HLA-C 的抑制性受体，也是高度多态性 KIR 家族的成员。由于其高 ADCC 潜力，适应性 NK 细胞可以在 SARS-CoV-2 感染中发挥关键作用，这种感染通常与强烈的 IgG 抗体反应相关。事实上，最近的研究表明，患有严重疾病的患者循环中适应性 NK 细胞的数量有所增加。重要的是，与传统 NK 细胞相比，适应性 NK 细胞可以持续存在多年，因此有可能有助于长期防止再次感染。在这个项目中，我们希望了解适应性 NKG2C+ NK 细胞如何影响 SARS-CoV-2 感染的结果。我们将在 COVID-19 恢复期患者 (MU) 以及 Covid-19 灵长类动物模型 (LW) 的样本中解决这个问题。杜塞尔多夫团队已经收集了超过 130 例 SARS-CoV-2 病例的样本和临床数据，并希望通过多色流式细胞术将相关临床参数（例如疾病严重程度、病毒载量、SARS-CoV-2 特异性 IgM 和 IgG 滴度以及 CMV 状态）与适应性 NK 细胞的存在相关联。此外，根据最近观察到的SARS-CoV-2刺突蛋白SP1导致肺上皮细胞中HLA-E的上调，我们将在体外探索这种机制是否会通过HLA-E/NKG2C轴刺激和扩增适应性NK细胞。德国灵长类动物中心 (DPZ) 的哥廷根团队已经基于新开发的针对猕猴 NKG2C 和 KIR 的单克隆抗体，证明了猕猴中存在类似的 CMV 相关扩增。因此，我们希望利用实验感染的恒河猴来研究适应性 NK 细胞在 SARS-CoV-2 感染急性期的作用。对血液样本和组织切片的分析将为我们提供独特的机会来监测适应性 NK 细胞在该灵长类动物模型中的分布和功能作用。如果适应性 NK 细胞确实参与了 SARS-CoV-2 感染的控制，那么这种可以在体外轻松扩展的先天免疫细胞类型可以为 COVID-19 患者的同种异体细胞治疗提供一个非常有趣的新选择。