Sars-Cov-2 May Hijack Gpcr Signaling Pathways To Compromise Lung Ion And Fluid Transport

The tropism of severe acute respiratory syndrome coronavirus 2 (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