SARS‐CoV‐2 May Hijack GPCR Signaling Pathways to Compromise Lung Ion and Fluid Transport

Abdel Hameid, Reem; Tambi, Richa; Nassir, Nasna; Begum, Ghausia; Zehra, Binte; Akter, Hosneara; Cormet‐Boyaka, Estelle; Kuebler, Wolfgang; Uddin, Mohammed; Berdiev, Bakhrom

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.