SARS-CoV-2 infects human pancreatic β-cells and elicits β-cell impairment. Wu et al.

Emerging evidence points towards an intricate relationship between the pandemic coronavirus disease 2019 (COVID-19) and diabetes. While pre-existing diabetes is associated with severe COVID-19, recent evidence suggests COVID-19 induces new-onset type 1 diabetes (T1D), convoluting diabetes as cause or consequence. To mechanistically link COVID-19 to T1D, we tested whether insulin-producing pancreatic β-cells can be infected by SARS-CoV-2 and cause β-cell depletion. We find the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, TRFC) are expressed in β-cells, with NRP1 selectively high. We discover that SARS-CoV-2 infects human pancreatic β-cells in patients who succumbed to COVID-19 and selectively infects human islet β-cells in vitro. We demonstrate SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces β-cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β-cell signaling, similar to T1D. Our study shows SARS-CoV-2 can directly induce β-cell killing, explaining T1D in COVID-19 patients.越来越多的研究证据表明，新型冠状病毒肺炎（COVID-19）与糖尿病之间存在复杂的关联。既往糖尿病与重症COVID-19密切相关，而最新研究证据显示，COVID-19可诱导新发1型糖尿病（T1D），使得糖尿病究竟作为病因还是结果变得错综复杂。为了从机制上将COVID-19与T1D联系起来，本研究探究了产胰岛素的胰腺β细胞是否可被严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染，并引发β细胞耗竭。本研究发现，SARS-CoV-2的受体血管紧张素转换酶2（ACE2）以及相关病毒入侵因子（TMPRSS2、NRP1、TRFC）在β细胞中均有表达，其中NRP1的表达水平显著升高。研究发现，死于COVID-19的患者体内的胰腺β细胞可被SARS-CoV-2感染，且在体外实验中，SARS-CoV-2可选择性感染人胰岛β细胞。实验证实，SARS-CoV-2感染可降低胰腺胰岛素含量与胰岛素分泌功能，并诱导β细胞凋亡，上述效应均可通过抑制NRP1得到逆转。对受感染胰岛进行磷酸化蛋白质组学通路分析后发现，其存在与T1D相似的β细胞凋亡信号通路。本研究证实，SARS-CoV-2可直接诱导β细胞死亡，这为COVID-19患者出现T1D的现象提供了机制层面的解释。