Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy.
Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy.
Cells. 2022 Apr 5;11(7):1235. doi: 10.3390/cells11071235.
The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19.
针对 SARS-CoV-2（COVID-19）的全球卫生紧急情况迫切需要开发新的治疗方法和治疗药物。在这项研究中，我们首次在人类细胞上测试了一种针对 Spike 蛋白的新型四价中和抗体（15033-7）和一种与宿主细胞上二肽基肽酶 4（DPP4）受体同源的合成肽。这两者都可能成为 COVID-19 治疗的强大免疫治疗候选物。感染始于近端气道，即远端肺部的肺泡 2 型（AT2）细胞，这些细胞表达 ACE2 和 DPP4 受体。因此，为了评估这两种方法的疗效，我们开发了源自人诱导多能干细胞（iPSC）的三维（3D）复杂肺类器官结构（hLORGs），并类似于体内器官。随后，hLORGs 被不同的 SARS-CoV-2 S 假病毒变体感染，并接受 Ab15033-7 或 DPP4 肽治疗。通过这两种方法，我们观察到病毒进入的显著减少，以及参与先天免疫和炎症反应的基因表达的调节。这些数据表明，这些方法在体外强烈降低感染效率方面是有效的，并且重要的是，提供了原理证明证据，表明 hiPSC 衍生的 hLORGs 代表了测试 COVID-19 治疗和预防方式的理想体外系统。
