Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany; Research Group "Cellular Polarity and Viral Infection," German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
Cell Metab. 2022 Jun 7;34(6):857-873.e9. doi: 10.1016/j.cmet.2022.04.009. Epub 2022 May 12.
It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.
目前尚不清楚为什么糖尿病患者更容易患上严重的 COVID-19。为此，我们建立了一种人类肾脏类器官模型，促进糖尿病肾病发展的早期特征。在感染 SARS-CoV-2 后，与对照组相比，糖尿病样肾脏类器官表现出更高的病毒载量。在对照或糖尿病样条件下，对肾脏类器官中血管紧张素转换酶 2（ACE2）的基因缺失可防止病毒检测。此外，与非糖尿病细胞相比，从糖尿病患者肾脏活检中分离出的细胞表现出改变的线粒体呼吸和增强的糖酵解，导致更高的 SARS-CoV-2 感染。相反，将患者细胞暴露于二氯乙酸（DCA），一种有氧糖酵解抑制剂，可导致 SARS-CoV-2 感染减少。我们的研究结果为鉴定肾脏中的糖尿病诱导的代谢编程作为增加 SARS-CoV-2 感染易感性的关键事件提供了新的见解，为针对能量代谢的 COVID-19 发病机制中的新干预措施的鉴定开辟了道路。
