Am J Physiol Lung Cell Mol Physiol

. 2021 Jan 12.
doi: 10.1152/ajplung.00499.2020. Online ahead of print.
SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport

Reem Abdel Hameid 1 , Estelle Cormet-Boyaka 2 , Wolfgang M Kuebler 3 , Mohammed Uddin 4 , Bakhrom K Berdiev 1



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.

Keywords: CFTR; COVID-19; ENaC; GPCR; SARS-CoV-2.