SARS-CoV-2 Spike protein enhances ACE2 expression via facilitating Interferon effects in bronchial epithelium

Abstract

Objective In this study, we focused on the interaction between SARS-CoV-2 and host Type I Interferon (IFN) response, so as to identify whether IFN effects could be influenced by the products of SARS-CoV-2. Methods All the structural and non-structural proteins of SARS-CoV-2 were transfected and overexpressed in the bronchial epithelial cell line BEAS-2B respectively, and typical antiviral IFN-stimulated gene (ISG) ISG15 expression was detected by qRT-PCR. RNA-seq based transcriptome analysis was performed between control and Spike (S) protein-overexpressed BEAS-2B cells. The expression of ACE2 and IFN effector JAK-STAT signaling activation were detected in control and S protein-overexpressed BEAS-2B cells by qRT-PCR or/and Western blot respectively. The interaction between S protein with STAT1 and STAT2, and the association between JAK1 with downstream STAT1 and STAT2 were measured in BEAS-2B cells by co-immunoprecipitation (co-IP). Results S protein could activate IFN effects and downstream ISGs expression. By transcriptome analysis, overexpression of S protein induced a set of genes expression, including series of ISGs and the SARS-CoV-2 receptor ACE2. Mechanistically, S protein enhanced the association between the upstream JAK1 and downstream STAT1 and STAT2, so as to promote STAT1 and STAT2 phosphorylation and ACE2 expression. Conclusion SARS-CoV-2 S protein enhances ACE2 expression via facilitating IFN effects, which may help its infection.

Understanding on the possible routes for SARS CoV-2 invasion via ACE2 in the host linked with multiple organs damage

“…As S-protein assists in the ACE2-receptor-mediated internalization of SARS-CoV-2, the host IFN responses could, thus, stimulate the capability of the virus to preserve cellular targets expression in neighboring epithelial cells ( Ziegler et al, 2020 ). Remarkably, screening of non-structural proteins plus structural proteins of SARS-CoV-2 supports the S-protein to facilitate the IFN-α effector, which further encourages the IFN-stimulated genes (ISGs) signaling and radically enhanced the production of long ACE2 protein in the bronchial epithelial cell line BEAS-2B ( Zhou et al, 2021 ), as depicted in Fig. 2 .…”

“…2 . Mechanistically, upregulation of long ACE2 protein was demonstrated with higher phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 as a result of reinforcing their signaling with upstream Janus kinase, i.e., JAK1, by S-protein of SARS-CoV-2 to aid viral access in the bronchial epithelium ( Zhou et al, 2021 ). Likewise, IFN-γ was noted to promote cellular differentiation into enterocytes expressing ACE2, supporting the high viral infection and replication ( Heuberger et al, 2021 ).…”

“…Additionally, rapidly growing literature also suggested the S-protein of SARS-CoV-2 contained a furin cleavage site, indicating that S-protein is highly susceptible for the activation beyond TMPRSS2 by a broad range of host proteases ( Bugge et al, 2009 ; Coutard et al, 2020 ; Walls et al, 2020 ). Besides, activation of IFN signalling induced by S-protein was also noted to support the elevated expression of ACE2 receptor, which may facilitate viral entry ( Zhou et al, 2021 ). Therefore, the cause of multiple organ damage in individuals affected with COVID-19 is suggested due to the involvement of multiple factors: direct viral role, inflammation, and immune responses against viral invasion, unbalanced in RAS and ACE2/angiotensin-(1–7)/MAS axis, and downregulation of ACE2 expression.…”

Maternal COVID-19 Vaccination and Its Potential Impact on Fetal and Neonatal Development

“…A study by Lei et al [57], for example, demonstrated that the spike protein down-regulated ACE2 in Syrian hamster vascular endothelial cells, which led to inhibited mitochondrial function and cell damage. In a later in vitro study, however, the spike protein was shown to upregulate bronchial epithelial cell ACE2 expression via activation of the Type I IFN signaling pathway [58]. These two studies indicate that the effect of this spike protein on ACE2 expression is tissue or species-specific.…”

The Evolutionary Dance between Innate Host Antiviral Pathways and SARS-CoV-2

“…Interestingly, ACE2 is also itself an ISG, and its expression is significantly induced by multiple IFN types, particularly β (I) and γ (II) [ 134 , 138 ]. Although one would assume this to be detrimental in the setting of SARS-CoV-2 infection (even the S protein itself has been shown to induce ACE2 expression) [ 139 ], in vitro studies have not shown that IFN induced ACE2 to enhance the virus’s replication, perhaps due to the other cellular defenses activated by the interferon response [ 138 ]. One study, however, showed that it was not the full ACE2 protein whose expression was induced by interferons, but rather a truncated isoform that did not possess the carboxylase function of ACE2 nor bind to SARS-CoV-2, and its exact function remains unknown [ 140 , 141 ].…”