Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Front Immunol. 2022 Jun 28;13:879033. doi: 10.3389/fimmu.2022.879033. eCollection 2022.
Clinical observations have shown that obesity is associated with the severe outcome of SARS-CoV-2 infection hallmarked by microvascular dysfunction in the lungs and other organs. Excess visceral fat and high systemic levels of adipose tissue (AT) derived mediators such as leptin and other adipokines have also been linked to endothelial dysfunction. Consequently, we hypothesized that AT-derived mediators may exacerbate microvascular dysfunction during of SARS-CoV-2 infection and tested this in a primary human lung microvascular endothelial (HLMVEC) cell model. Our results indicate that HLMVEC are not susceptible to SARS-CoV-2 infection since no expression of viral proteins and no newly produced virus was detected. In addition, exposure to the virus did not induce endothelial activation as evidenced by a lack of adhesion molecule, E-selectin, VCAM-1, ICAM-1, and inflammatory cytokine IL-6 induction. Incubation of endothelial cells with the pro-inflammatory AT-derived mediator, leptin, prior to virus inoculation, did not alter the expression of endothelial SARS-CoV-2 entry receptors and did not alter their susceptibility to infection. Furthermore, it did not induce inflammatory activation of endothelial cells. To verify if the lack of activated phenotype in the presence of adipokines was not leptin-specific, we exposed endothelial cells to plasma obtained from critically ill obese COVID-19 patients. Plasma exposure did not result in E-selectin, VCAM-1, ICAM-1, or IL-6 induction. Together our results strongly suggest that aberrant inflammatory endothelial responses are not mounted by direct SARS-CoV-2 infection of endothelial cells, even in the presence of leptin and other mediators of obesity. Instead, endothelial activation associated with COVID-19 is likely a result of inflammatory responses initiated by other cells. Further studies are required to investigate the mechanisms regulating endothelial behavior in COVID-19 and the mechanisms driving severe disease in obese individuals.
临床观察表明，肥胖与 SARS-CoV-2 感染的严重后果有关，其特征是肺部和其他器官的微血管功能障碍。过多的内脏脂肪和高水平的全身脂肪组织（AT）衍生介质，如瘦素和其他脂肪因子，也与内皮功能障碍有关。因此，我们假设 AT 衍生的介质可能会在 SARS-CoV-2 感染期间加剧微血管功能障碍，并在原代人肺微血管内皮（HLMVEC）细胞模型中对此进行了测试。
我们的研究结果表明，HLMVEC 不易感染 SARS-CoV-2，因为未检测到病毒蛋白的表达和新产生的病毒。此外，暴露于病毒不会诱导内皮细胞活化，这表现在缺乏粘附分子 E-选择素、VCAM-1、ICAM-1 和炎症细胞因子 IL-6 的诱导。在接种病毒之前，将内皮细胞与促炎的 AT 衍生介质瘦素孵育，不会改变内皮细胞 SARS-CoV-2 进入受体的表达，也不会改变其感染易感性。此外，它不会诱导内皮细胞的炎症激活。为了验证在存在脂肪因子的情况下缺乏激活表型是否不是瘦素特异性的，我们将内皮细胞暴露于从重症肥胖 COVID-19 患者中获得的血浆中。血浆暴露不会导致 E-选择素、VCAM-1、ICAM-1 或 IL-6 的诱导。
总之，我们的研究结果强烈表明，即使存在瘦素和肥胖的其他介质，内皮细胞也不会通过 SARS-CoV-2 的直接感染产生异常炎症反应。相反，与 COVID-19 相关的内皮激活可能是由其他细胞引发的炎症反应的结果。需要进一步的研究来探讨调节 COVID-19 内皮行为的机制以及导致肥胖个体发生严重疾病的机制。
