SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication, 2023, Montezano et al.

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication
Montezano, Augusto C.; Camargo, Livia L.; Mary, Sheon; Neves, Karla B; Rios, Francisco J; Stein, Ross; Lopes, Rheure A.; Beattie, Wendy; Thomson, Jacqueline; Herder, Vanessa; Szemiel, Agnieszka M.; McFarlane, Steven; Palmarini, Massimo; Touyz, Rhian M.

COVID‑19, caused by SARS‑CoV‑2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS‑CoV‑2 may be important.

Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process. Human endothelial cells were exposed to SARS‑CoV‑2 spike protein, S1 subunit (rS1p) and pro‑inflammatory signaling and inflammatory mediators assessed. ACE2 was modulated pharmacologically and by siRNA. Endothelial cells were also exposed to SARS‑CoV‑2. rSP1 increased production of IL‑6, MCP‑1, ICAM‑1 and PAI‑1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury. ACE2 interacting proteins involved in inflammation and RNA biology were identified in rS1p‑treated cells. Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS‑CoV‑2 virus did not exhibit viral replication.

We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID‑19‑ associated endotheliitis.

Link | PDF (Nature Scientific Reports)

 

GRP78 / BiP is important in holding back or activating the ER stress response. It binds to the 3 trans-membrane ER stress sensors (IRE1⍺, PERK, ATF6⍺). However, it preferentially binds to mis-folded proteins in the ER lumen and this competes with the stress sensors. So, once dissociated from BiP, eg PERK is phosphorylated, which leads to phosphorylation of eIF2⍺, which activates that arm of the unfolded protein response (UPR). That has two mechanisms: phosphorylation of eIF2⍺ ceases ribosomal translation of mRNA into proteins (to reduce the ongoing ER protein overload); but also upregulates ATF4 which induces CHOP which upregulates ER chaperones and foldases to try and clear the misfolded junk already in the ER lumen.

Phew. See Endoplasmic Reticulum ER Stress Response Failure in Diseases (2020).



In WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (2023) —

Back to Endoplasmic Reticulum (ER) Stress Response Failure in Diseases (2020) —

If I'm following this correctly, and if something similar to the ME/CFS findings is happening in LC, my questions would be:

if spike protein can bind to GRP78 / BiP, can this occur in the ER? And could this lead to the equivalent of a severe ER stress condition, where BiP is preferentially binding to spike + any misfolded proteins and overloading the UPR activation, leading to downstream failure? (ie ER stress response failure).

 

I wonder whether something similar could happen with other viruses that are known to trigger ME/CFS?
I haven’t read the paper just saw some discussion.

Also saw it suggested that this might have implications for vaccines.

 

Painful to say in public, as I have always been very pro vaccine, but n=1 for Pfizer spike protein here

 

See also Identification of a Druggable Site on GRP78 at the GRP78-SARS-CoV-2 Interface and Compounds to Disrupt that Interface (2023, Preprint: BioRxiv)