Kalejaiye Titilola D, Bhattacharya Rohan, Burt Morgan A, Travieso Tatianna, Okafor Arinze E, Mou Xingrui, Blasi Maria, Musah Samira
Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States.
Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC, United States.
Front Cell Dev Biol. 2022 Apr 20;10:855340. doi: 10.3389/fcell.2022.855340. eCollection 2022.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发了2019冠状病毒病（COVID-19），该疾病已在全球导致超过590万人死亡。虽然呼吸系统中的细胞是SARS-CoV-2的初始靶标，但越来越多的证据表明COVID-19是一种多器官疾病。然而，SARS-CoV-2对其他器官（如肾脏）细胞的直接亲和力仍知之甚少，而肾脏在重症COVID-19中常常是受累器官。我们采用了一种人类诱导多能干细胞（iPS）衍生模型来研究SARS-CoV-2对肾小球足细胞的亲和力，并检测了病毒结合和加工的宿主因子的表达。我们研究了活的SARS-CoV-2病毒以及假型病毒的细胞摄取情况。用活的SARS-CoV-2或刺突假型慢病毒颗粒感染足细胞，结果显示即使在低感染复数（MOI）为0.01时也能发生细胞摄取。我们发现SARS-CoV-2病毒直接感染人类iPS细胞衍生的足细胞可导致细胞死亡和足细胞足突回缩，这是足细胞病和进行性肾小球疾病（包括在重症COVID-19患者中观察到的塌陷性肾小球病）的一个标志。我们确定BSG/CD147和ACE2受体是人类iPS细胞衍生足细胞中刺突结合活性的关键介质。这些结果表明，SARS-CoV-2可通过多种结合相互作用和伙伴感染肾小球足细胞，这可能是SARS-CoV-2对肾脏组织具有高亲和力的基础。这种干细胞衍生模型可能有助于进行肾脏特异性抗病毒药物筛选以及COVID-19器官嗜性的机制研究。
