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.

天然杀手（NK）细胞是针对急性病毒感染的第一道防线的一部分。最近，鉴定出一种新型的病毒特异性自适应NK细胞，该细胞在急性巨细胞病毒（CMV）感染过程中扩展，通常对IgG抗体刺激过度敏感，从而导致高效且快速抗体介导的细胞毒性（ADCC）。这些适应性（也称为记忆）NK细胞的标志是刺激受体NKG2C的表达，该表达是针对人白细胞抗原E（HLA-E）的特异性的。我们最近表明，在30-40％的HCMV+病例中，自适应NKG2C+ NK细胞稳定地保持为较大的克隆膨胀。此外，我们已经表明，这些膨胀的大小与KIR2DL受体的共表达相关，KIR2DL受体是HLA-C的抑制受体和高度多态KIR家族的成员。由于其高ADCC潜力，自适应NK细胞可能在SARS-COV-2感染中起关键作用，这通常与强IgG抗体反应有关。实际上，最近表明患有严重疾病的患者在循环中增加了自适应NK细胞的存在。重要的是，与常规NK细胞相比，自适应NK细胞可以持续多年，因此有可能有助于长期保护重新感染。在这个项目中，我们想了解自适应NKG2C+ NK细胞如何影响SARS-COV-2感染的结果。我们将在COVID-19患者（MU）以及Covid-19（LW）的私人模型中的样本中解决此问题。杜塞尔多夫团队已经在> 130个SARS-COV-2病例上收集了样本和临床数据，并希望将相关的临床参数（例如疾病严重程度，病毒载荷，SARS-COV-2特异性IGM和IgG滴度）以及CMV状态与多微型循环的适应性NK细胞的存在相关联。此外，基于最近的观察结果，即SARS-COV-2尖峰蛋白SP1导致HLA-E在肺上皮细胞中的上调，如果这种机制通过HLA-E/NKG2C Axis刺激和扩展自适应NK细胞，我们将在体外探索体外。德国灵长类动物中心（DPZ）的哥廷根团队已经可以证明，根据针对Macaque NKG2C和KIR的新开发的MABS，猕猴中有类似CMV相关的扩张。因此，我们想研究使用实验感染的恒河猕猴在SARS-COV-2感染的急性阶段自适应NK细胞的贡献。血液样本和组织切片的分析将为我们提供独特的机会，以监测自适应NK细胞在该私有模型中的分布和功能作用。如果自适应NK细胞确实参与了SARS-COV-2感染的控制，那么这种先天的免疫细胞类型可以轻松地在体外扩展，可以为COVID-19患者的同种异体细胞治疗提供一种非常有趣的新颖选择。