Wang Hao, Yuan Zixuan, Pavel Mahmud Arif, Jablonski Sonia Mediouni, Jablonski Joseph, Hobson Robert, Valente Susana, Reddy Chakravarthy B, Hansen Scott B
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA.
bioRxiv. 2021 Jun 28:2020.05.09.086249. doi: 10.1101/2020.05.09.086249.
Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the entry of pseudotyped SARS-CoV-2 and the infectivity of the virion. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol shows almost twice the total number of endocytic entry points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the endocytic entry site where SARS-CoV-2 presumably docks to efficiently exploit entry into the cell. Furthermore, in cells producing virus, cholesterol optimally positions furin for priming SARS-CoV-2, producing a more infectious virion with improved binding to the ACE2 receptor. In vivo, age and high fat diet induces cholesterol loading by up to 40% and trafficking of ACE2 to endocytic entry sites in lung tissue from mice. We propose a component of COVID19 severity based on tissue cholesterol level and the sensitivity of ACE2 and furin to cholesterol. Molecules that reduce cholesterol or disrupt ACE2 localization with viral entry points or furin localization in the producer cells, may reduce the severity of COVID19 in obese patients.
2019冠状病毒病（COVID-19）是一种由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的呼吸道感染，该病毒于2019年起源于中国武汉。这种疾病在老年人和患有基础慢性病的人群中尤为严重。一种解释为何老年人易感染而儿童具有抵抗力的分子机制在很大程度上尚不清楚。在此，我们展示了利用胆固醇转运蛋白载脂蛋白E（apoE）将血清中的胆固醇加载到细胞中，可增强假型SARS-CoV-2的进入及病毒粒子的感染性。对具有高胆固醇的SARS-CoV-2进入点进行超分辨率成像显示，内吞进入点的总数几乎增加了一倍。胆固醇同时将血管紧张素原转化酶（ACE2）转运至内吞进入位点，SARS-CoV-2可能在此处停靠，从而有效地利用该位点进入细胞。此外，在产生病毒的细胞中，胆固醇能使弗林蛋白酶最佳定位，从而启动SARS-CoV-2，产生一种与ACE2受体结合力增强且感染性更强的病毒粒子。在体内，年龄和高脂肪饮食会使胆固醇加载量增加高达40%，并使ACE2从小鼠肺组织转运至内吞进入位点。我们提出，基于组织胆固醇水平以及ACE2和弗林蛋白酶对胆固醇的敏感性，这是导致COVID-19严重程度的一个因素。降低胆固醇或破坏ACE2在病毒进入点的定位或破坏其在产生病毒的细胞中弗林蛋白酶定位的分子，可能会降低肥胖患者中COVID-19的严重程度。
