Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
Team SMMU-China of the International Genetically Engineered Machine (iGEM) Competition, Department of Biophysics, Second Military Medical University, Shanghai, China.
Front Immunol. 2021 Jul 23;12:669103. doi: 10.3389/fimmu.2021.669103. eCollection 2021.
Targeted therapeutics for the treatment of coronavirus disease 2019 (COVID-19), especially severe cases, are currently lacking. As macrophages have unique effector functions as a first-line defense against invading pathogens, we genetically armed human macrophages with chimeric antigen receptors (CARs) to reprogram their phagocytic activity against SARS-CoV-2. After investigation of CAR constructs with different intracellular receptor domains, we found that although cytosolic domains from MERTK (CAR) did not trigger antigen-specific cellular phagocytosis or killing effects, unlike those from MEGF10, FcRγ and CD3ζ did, these CARs all mediated similar SARS-CoV-2 clearance . Notably, we showed that CAR macrophages reduced the virion load without upregulation of proinflammatory cytokine expression. These results suggest that CAR drives an 'immunologically silent' scavenger effect in macrophages and pave the way for further investigation of CARs for the treatment of individuals with COVID-19, particularly those with severe cases at a high risk of hyperinflammation.
针对 2019 年冠状病毒病（COVID-19），特别是重症病例的靶向治疗方法目前仍较为缺乏。由于巨噬细胞作为抵御入侵病原体的第一道防线具有独特的效应功能，我们通过嵌合抗原受体（CAR）对人巨噬细胞进行基因改造，以重新编程其针对 SARS-CoV-2 的吞噬活性。在对具有不同细胞内受体结构域的 CAR 构建体进行研究后，我们发现尽管来自 MERTK（CAR）的细胞质结构域不会触发针对特定抗原的细胞吞噬或杀伤作用，与来自 MEGF10、FcRγ和 CD3ζ 的结构域不同，但这些 CAR 均介导了类似的 SARS-CoV-2 清除。值得注意的是，我们表明 CAR 巨噬细胞在不增加促炎细胞因子表达的情况下降低了病毒粒子负荷。这些结果表明，CAR 在巨噬细胞中驱动了一种“免疫沉默”的清道夫作用，并为进一步研究 CAR 治疗 COVID-19 患者，特别是那些有高炎症风险的重症患者铺平了道路。
