School of Biosciences, Sir Martin Evans Building, Cardiff University, Wales CF10 3AX, UK.
Function (Oxf). 2022 Jan 31;3(2):zqac002. doi: 10.1093/function/zqac002. eCollection 2022.
The S protein subunit 1 (S1) of SARS-CoV-2 is known to be responsible for the binding of the virus to host cell receptors, but the initial intracellular signalling steps following receptor activation of cells in the exocrine pancreas are unknown. Using an intact live mouse pancreatic lobule preparation, we observed that S1 elicited Ca signals in stellate cells and macrophages, but not in the dominant acinar cells. The Ca signals occurred mostly in the form of repetitive Ca spikes. The probability of observing Ca signals depended on the S1 concentration. The threshold was close to 70 nM, whereas at 600 nM, all cells responded. The SARS-Cov-2 nucleocapsid protein did not elicit any Ca signals in any of the three cell types tested. The S1-induced Ca signals in stellate cells started much faster (122 ± 37s) than those in macrophages (468 ± 68s). Furthermore, the interleukin-18 binding protein (IL-18BP) abolished the responses in macrophages without affecting the Ca signals in stellate cells. The S1-elicited Ca signals were completely dependent on the presence of external Ca and were abolished by a selective inhibitor (CM4620) of Orai1 Ca Release Activated Ca channels. SARS-CoV-2 may contribute to acute pancreatitis, an often fatal inflammatory human disease. The S1-elicited Ca signals we have observed in the pancreatic stellate cells and endogenous macrophages may play an important part in the development of the inflammatory process.
SARS-CoV-2 的 S 蛋白亚单位 1（S1）已知负责病毒与宿主细胞受体的结合，但细胞外分泌胰腺中受体激活后最初的细胞内信号步骤尚不清楚。使用完整的活鼠胰腺小叶制备物，我们观察到 S1 在星状细胞和巨噬细胞中引起 Ca 信号，但在主导的腺泡细胞中没有引起。Ca 信号主要以重复的 Ca spikes 形式出现。观察到 Ca 信号的概率取决于 S1 浓度。阈值接近 70 nM，而在 600 nM 时，所有细胞均有反应。在测试的三种细胞类型中，SARS-CoV-2 核衣壳蛋白均未引起任何 Ca 信号。S1 诱导的星状细胞中的 Ca 信号开始得更快（122±37s），而巨噬细胞中的 Ca 信号开始得更慢（468±68s）。此外，白细胞介素-18 结合蛋白（IL-18BP）消除了巨噬细胞中的反应，而不影响星状细胞中的 Ca 信号。S1 诱导的 Ca 信号完全依赖于外部 Ca 的存在，并且被 Orai1 Ca 释放激活 Ca 通道的选择性抑制剂（CM4620）所消除。SARS-CoV-2 可能导致急性胰腺炎，这是一种经常致命的人类炎症性疾病。我们在胰腺星状细胞和内源性巨噬细胞中观察到的 S1 诱导的 Ca 信号可能在炎症过程的发展中起重要作用。
