Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Physiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cell Mol Gastroenterol Hepatol. 2024;18(5):101383. doi: 10.1016/j.jcmgh.2024.101383. Epub 2024 Jul 31.
BACKGROUND & AIMS: Diarrhea occurs in up to 50% of cases of COVID-19. Nonetheless, the pathophysiologic mechanism(s) have not been determined.
This was examined using normal human enteroid monolayers exposed apically to live SARS-CoV-2 or non-replicating virus-like particles (VLPs) bearing the 4 SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes.
Live virus and VLPs incrieased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3, and DRA. Interleukin (IL)-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA and protein. Neither VLPs nor IL-6 plus IL-8 alone altered Cl secretion, but together they caused Cl secretion, which was Ca-dependent, CFTR-independent, blocked partially by a specific TMEM16A inhibitor, and entirely by a general TMEM16 family inhibitor. VLPs and irradiated virus, but not IL-6 plus IL-8, produced Ca waves that began within minutes of VLP exposure, lasted for at least 60 minutes, and were prevented by pretreatment with apyrase, a P2Y1 receptor antagonist, and general TMEM16 family inhibitor but not by the specific TMEM16A inhibitor.
The pathophysiology of COVID-19 diarrhea appears to be a unique example of a calcium-dependent inflammatory diarrhea that is caused by direct viral effects plus the virus-induced intestinal epithelial cytokine secretion.
多达 50%的 COVID-19 病例会出现腹泻。然而，其病理生理机制尚未确定。
本研究采用正常的人肠类器官单层细胞，将其顶端暴露于活 SARS-CoV-2 或携带 4 种 SARS-CoV-2 结构蛋白的非复制病毒样颗粒（VLPs）或照射后的病毒，所有这些都会与肠细胞结合并进入肠细胞。
活病毒和 VLPs 增加了多种细胞因子的分泌，并降低了 ACE2、NHE3 和 DRA 的 mRNA。白细胞介素（IL）-6 加 IL-8 单独降低了 NHE3 mRNA 和蛋白以及 DRA mRNA 和蛋白。VLPs 或 IL-6 加 IL-8 单独作用均不改变 Cl 分泌，但两者共同作用可导致 Cl 分泌，这种分泌依赖于 Ca2+，与 CFTR 无关，可被特定的 TMEM16A 抑制剂部分阻断，也可被通用的 TMEM16 家族抑制剂完全阻断。VLPs 和照射后的病毒，但不是 IL-6 加 IL-8，可产生 Ca2+波，这种 Ca2+波在 VLPs 暴露后的几分钟内开始，至少持续 60 分钟，可被 P2Y1 受体拮抗剂和通用 TMEM16 家族抑制剂预先处理所阻断，但不能被特异性的 TMEM16A 抑制剂所阻断。
COVID-19 腹泻的病理生理学似乎是一种独特的钙依赖性炎症性腹泻的例子，由直接的病毒作用加上病毒诱导的肠道上皮细胞细胞因子分泌引起。
