The tropism of SARS-CoV-2, a virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, towards the host cells is determined, at least in part, by the expression and distribution of its cell surface receptor, angiotensin-converting enzyme 2 (ACE2). The virus further exploits the host cellular machinery to gain access into the cells; its spike protein is cleaved by a host cell surface transmembrane serine protease 2 (TMPRSS2) shortly after binding ACE2 followed by its proteolytic activation at a furin cleavage site. The virus primarily targets the epithelium of the respiratory tract which is covered by a tightly regulated airway surface liquid (ASL) layer that serves as a primary defense mechanism against respiratory pathogens. The volume and viscosity of this fluid layer is regulated and maintained by a coordinated function of different transport pathways in the respiratory epithelium. We argue that SARS-CoV-2 may potentially alter evolutionary conserved second-messenger signaling cascades via activation of G-protein coupled receptors (GPCRs) or by directly modulating G protein signaling. Such signaling may in turn adversely modulate transepithelial transport processes, especially those involving cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial Na⁺ channel (ENaC), thereby shifting the delicate balance between anion secretion and sodium absorption that controls homeostasis of this fluid layer. As a result, activation of the secretory pathways including CFTR-mediated Cl^- transport may overwhelm the absorptive pathways such as ENaC-dependent Na⁺ uptake and initiate a pathophysiological cascade leading to lung edema, one of the most serious and potentially deadly clinical manifestations of COVID-19.

中文翻译：

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SARS-CoV-2 可能会劫持 GPCR 信号通路来失调肺离子和液体运输

SARS-CoV-2（一种导致 2019 年冠状病毒病（COVID-19）大流行的病毒）对宿主细胞的趋向性至少部分取决于其细胞表面受体血管紧张素的表达和分布。转化酶 2 (ACE2)。病毒进一步利用宿主细胞机制进入细胞；它的刺突蛋白在结合 ACE2 后不久被宿主细胞表面跨膜丝氨酸蛋白酶 2 (TMPRSS2) 切割，然后在弗林蛋白酶切割位点进行蛋白水解激活。该病毒主要针对呼吸道上皮细胞，该上皮细胞被严格调控的气道表面液体 (ASL) 层覆盖，该层用作抵御呼吸道病原体的主要防御机制。该流体层的体积和粘度由呼吸上皮中不同运输途径的协调功能调节和维持。我们认为，SARS-CoV-2 可能通过激活 G 蛋白偶联受体 (GPCR) 或直接调节 G 蛋白信号传导来改变进化保守的第二信使信号级联。这种信号可能反过来不利地调节跨上皮转运过程，尤其是那些涉及囊性纤维化跨膜电导调节器 (CFTR) 和上皮 Na⁺通道 (ENaC)，从而改变阴离子分泌和钠吸收之间的微妙平衡，控制该流体层的稳态。因此，包括 CFTR 介导的 Cl ^-转运在内的分泌途径的激活可能会压倒吸收途径，例如 ENaC 依赖的 Na ⁺摄取并启动导致肺水肿的病理生理级联反应，这是肺水肿最严重和可能致命的临床表现之一。新型冠状病毒肺炎（COVID-19）：新冠肺炎（COVID-19）：COVID-19。