I didn’t have time to read your link, Cathi, so pardon my impertinence.
Is this saying that any interaction with the ACE2 binding site, triggers the innards of the cell to begin other processes, even when the furin cleavage site is not involved (i.e., the virus never even *enters* the cell) ?
If so, this would go a LONG way towards teasing out a putative mechanism for adverse events subsequent to injection with the mRNA.
In particular, the body is not static; a paper out of Harvard I posted a snippet or link from yesterday, pointed out that the body downregulates ACE2 receptors in the uterus during pregnancy, which happily helps protect the growing baby from COVID during early pregnancy.
But if there is such a thing as downregulation, then there may be upregulation. More ACE2 receptors...I vaguely remember papers from before the c00f left China, showing that Chinese males (I think especially smokers) had many more ACE2 binding sites in their lungs than other groups.
Thanks for posting this.
Might’ve said placenta not uterus. No biggie, as it was only an example of the *kind* of thing I meant.
The SARS-CoV-2 spike protein, a class I viral fusion protein, is critical to initiating the interactions between the virus and the host cell surface receptor, facilitating viral entry into the host cell by assisting in the fusion of the viral and host cell membranes. This protein consists of two subunits: Subunit 1 (S1) that contains the ACE2 receptor-binding domain (RBD) and Subunit 2 (S2) that plays a role in the fusion process [3,4] (Figure 1). The SARS-CoV-2 spike protein is the major target for the development of COVID-19 vaccines.
While ACE2 is now well known as a ‘receptor’ to which the SARS-CoV-2 spike protein binds on human host cells in order to facilitate the membrane fusion and gain viral entry, the usual physiological function of ACE2 is not to serve as a membrane receptor to transduce intracellular signals. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving angiotensin II to angiotensin (1–7) and regulating blood pressure [24,25] (Figure 2).
However, ten years ago, Chen et al. [26] reported the intriguing findings showing that ACE2 acts as a membrane receptor for cell signal transduction in response to the spike protein of SARS-CoV (now also known as SARS-CoV-1, the virus that caused the SARS outbreak in 2002–2004) in the human lung alveolar epithelial cell line, A549. The spike protein of SARS-CoV-1 is 76–78% identical to that of SARS-CoV-2 [27]. In their study, it was shown that the binding of the full-length spike protein to ACE2 triggered the casein kinase II-dependent activation of activator protein-1 (AP-1) transcription factor and subsequent gene transcriptional events [26].
Their finding on SARS-CoV-1 [26] and ours on SARS-CoV-2 [21] indicate that the spike protein remarkably functionally converts ACE2 (that is normally a peptidase enzyme) into a membrane receptor for cell signaling that uses the spike protein as a ligand for its activation
Kuba et al. [28] showed that the injection of mice with recombinant SARS-CoV-1 spike protein reduced the ACE2 expression and worsened the acid-induced lung injury. In mice with an acid-induced lung injury, the recombinant SARS-CoV-1 spike protein dramatically increased angiotensin II, and the angiotensin receptor inhibitor losartan attenuated the spike protein-induced enhancement of lung injury [28].
Thus, these in vivo studies demonstrated that the spike protein of SARS-CoV-1 (without the rest of the virus) reduces the ACE2 expression, increases the level of angiotensin II, and exacerbates the lung injury.
The SARS-CoV-2 spike protein without the rest of the viral components has also been shown to activate cell signaling by Patra et al. [29]. The authors reported that the full-length SARS-CoV-2 spike protein expressed by the means of transient transfection, either in the human lung alveolar epithelial cell line A549 or in the human liver epithelial cell line Huh7.5, activated NF-κB and AP-1 transcription factors as well as p38 and ERK mitogen-activated protein kinases, releasing interleukin-6. This cell signaling cascade was found to be triggered by the SARS-CoV-2 spike protein downregulating the ACE2 protein expression, subsequently activating the angiotensin II type 1 receptor [29]. These experiments using transient transfection may reflect the intracellular effects of the spike protein that could be triggered by the RNA- and viral vector-based vaccines.
These results collectively reinforce the idea that human cells are sensitively affected by the extracellular and/or intracellular spike proteins though the activation of cell signal transduction.