Stabilizing Cellular Barriers: Raising the Shields Against COVID-19

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its clinical manifestation (COVID-19; coronavirus disease 2019) have caused a worldwide health crisis. Disruption of epithelial and endothelial barriers is a key clinical turning point that differentiates patients who are likely to develop severe COVID-19 outcomes: it marks a significant escalation in respiratory symptoms, loss of viral containment and a progression toward multi-organ dysfunction. These barrier mechanisms are independently compromised by known COVID-19 risk factors, including diabetes, obesity and aging: thus, a synergism between these underlying conditions and SARS-CoV-2 mechanisms may explain why these risk factors correlate with more severe outcomes. This review examines the key cellular mechanisms that SARS-CoV-2 and its underlying risk factors utilize to disrupt barrier function. As an outlook, we propose that glucagon-like peptide 1 (GLP-1) may be a therapeutic intervention that can slow COVID-19 progression and improve clinical outcome following SARS-CoV-2 infection. GLP-1 signaling activates barrier-promoting processes that directly oppose the pro-inflammatory mechanisms commandeered by SARS-CoV-2 and its underlying risk factors.

Keywords: acute respiratory and circulatory disruption; endothelial barrier disruption; enteroendocrine; glucagon like peptide 1 (GLP-1); immune cells; lung; tumor necrosis factor (TNF); tumor necrosis factor converting enzyme (TACE).

Figure 1

Increased TACE activity in COVID-19 shifts barrier cells toward a pro-inflammatory, pro-coagulatory and permissive state. In healthy cells, TACE is predominantly inactive, thereby permitting anti-inflammatory signals via TACE substrates, including ACE2, TNF, and EPCR. ACE2, a key player in the RAAS system, converts angiotensin II (AngII) into angiotensin-1-7 [Ang (–7)]: the subsequent activation of AT2R and Mas receptors stimulates anti-inflammatory signals. When ACE2 is cleaved, angiotensin signaling shifts from AT2R/Mas receptors to the pro-inflammatory AT1R. TNF receptors stimulate differential signals, depending on whether the receptor is activated by the membrane-bound or soluble form of TNF: membrane bound TNF elicits important anti-inflammatory signals; in contrast, soluble TNF mediates pro-inflammatory signals. Finally, EPCR plays a critical role in regulating coagulation by converting inactive protein C (PC) into activated protein C (APC). Activated protein C subsequently inactivates pro-coagulatory factors; it also cleaves PAR1 and transactivates S1PR, resulting anti-inflammatory and barrier-stabilizing signals. TACE-dependent EPCR cleavage prevents the activation of PC, leading to reduced capacity to inhibit coagulation; RhoA-dependent signaling via uncleaved PAR1 is barrier destabilizing. TACE, tumor necrosis factor alpha converting enzyme; ACE2, angiotensin converting enzyme 2; TNF, tumor necrosis factor; EPCR, endothelial protein C receptor; RAAS, rennin-angiotensin-aldosterone system; AT2R, angiotensin receptor 2; AT1R, angiotensin receptor 1; PAR1, protease activated receptor 1; S1PR, sphingosine-1-phosphate receptor; TNFR, TNF receptor. Created with BioRender.com.

Figure 2

Proposed mechanisms for GLP-1-mediated stabilization of alveolar epithelial and endothelial barriers in COVID-19. In COVID-19, alveolar epithelial cells are severely damaged by direct viral attack and the immune response, leading to hyaline membrane formation, increased barrier permeability, alveolar fluid accumulation and a loss of viral containment. Viral attack on the underlying endothelial cells leads to TACE activation that: augments pro-inflammatory signaling, increases endothelial barrier permeability, promotes immune cell adhesion/extravasation and compromises EPCR-dependent regulation of coagulation. Notably, the loss of endothelial barrier integrity further exacerbates alveolar fluid accumulation. GLP-1 receptor signaling directly opposes these pathological mechanisms by: attenuating TACE expression/activity, initiating counteracting anti-inflammatory signals, promoting barrier function via increased tight junction expression and stimulating surfactant secretion (reduces alveolar fluid accumulation by decreasing surface tension). The GLP-1 mediated attenuation of TACE activity/expression is also expected to hinder viral entry into cells. GLP-1, glucagon like peptide 1; ACE2, angiotensin converting enzyme 2; TACE, tumor necrosis factor alpha converting enzyme; TNF, tumor necrosis factor; EPCR, endothelial protein C receptor. Created with BioRender.com.