Thrombogenesis in COVID-19 is Caused by Spike Proteins Activating NOX2-p66SHC Axis via Inhibiting SLAMF8
Nikhil Prasad Fact checked by:Thailand Medical News Team Jan 07, 2025 1 day, 4 hours, 42 minutes ago
Medical News: A groundbreaking study from researchers at Jilin University and The First Hospital of Jilin University in China has unveiled critical insights into the mechanisms behind thrombogenesis in COVID-19. Thrombosis, or the formation of blood clots, is a life-threatening complication often observed in patients infected with SARS-CoV-2, the virus responsible for COVID-19. These findings shed light on how the spike protein of the virus disrupts cellular processes to promote clot formation, offering new avenues for therapeutic interventions.
Thrombogenesis in COVID-19 is Caused by Spike Proteins Activating NOX2-p66SHC Axis
via Inhibiting SLAMF8
Spike Protein’s Role in Thrombosis
The SARS-CoV-2 spike protein, known for its role in enabling the virus to infect human cells, has been found to play a key role in thrombogenesis. The research highlights that the spike protein induces excessive production of reactive oxygen species (ROS) within endothelial cells. This
Medical News report elaborates that the elevated ROS disrupts mitochondrial dynamics, leading to endothelial cell damage and the transformation of these cells into a pro-thrombotic phenotype. This transformation is characterized by increased expression of thrombogenic factors such as von Willebrand factor (VWF), intercellular adhesion molecules (ICAM), and coagulation factors, which collectively exacerbate blood clot formation.
The study demonstrates that the spike protein achieves these effects by inhibiting the expression of SLAMF8 (Signaling Lymphocytic Activation Molecule Family 8), a crucial regulatory protein in endothelial cells. The suppression of SLAMF8 activates the NOX2-p66SHC axis - a pathway that perpetuates oxidative stress and mitochondrial damage - creating a vicious cycle that promotes thrombosis.
Key Findings from the Study
-Increased ROS Production
Using human aortic endothelial cells (HAECs) treated with the recombinant spike protein, the researchers observed a significant increase in ROS production. This oxidative stress disrupted the mitochondrial membrane potential and increased mitochondrial fragmentation - hallmarks of cellular damage.
-The NOX2-p66SHC Axis
The study uncovered the role of the NOX2-p66SHC axis in this process. NOX2, a membrane-bound enzyme, produces superoxide anions, which are precursors to ROS. The activation of p66SHC, a mitochondrial adapter protein, amplifies ROS production by disrupting the electron transport chain in mitochondria. The spike protein’s suppression of SLAMF8 appears to directly influence the activation of this pathway, further exacerbating endothelial damage.
Therapeutic Interventions
To counteract these effects, the researchers tested several interventions. They demonstrated that:
-Mitoquinone (MitoQ), a ROS scavenger, significantly reduced oxidative stress and restored mitocho
ndrial function.
-Midivi-1, a mitochondrial fission inhibitor, reversed the pro-thrombotic phenotype induced by the spike protein.
Overexpression of SLAMF8 in endothelial cells mitigated ROS production, improved mitochondrial dynamics, and reduced thrombotic factor expression.
These findings underscore the therapeutic potential of targeting oxidative stress and mitochondrial dysfunction to prevent COVID-19-associated thrombosis.
In Vivo Validation
In a mouse model, the researchers used an adeno-associated virus to overexpress SLAMF8 in endothelial cells. These mice were then exposed to the spike protein and subjected to a ferric chloride-induced thrombosis test. The results showed that SLAMF8 overexpression reversed the spike protein’s effects, reducing blood flow obstruction and platelet aggregation. This in vivo validation highlights SLAMF8’s protective role against thrombogenesis.
Clinical Implications
Data from COVID-19 patients provided further support for these findings. Single-cell RNA sequencing analysis revealed a strong negative correlation between SLAMF8 expression and thrombosis risk in endothelial cells. COVID-19 patients exhibited reduced SLAMF8 levels and elevated expression of thrombogenic markers, such as PAI-1 and SELP, compared to healthy controls.
Conclusions
The study identifies a novel mechanism by which the SARS-CoV-2 spike protein promotes thrombogenesis by suppressing SLAMF8 and activating the NOX2-p66SHC axis. This discovery not only deepens our understanding of COVID-19’s vascular complications but also opens the door to potential therapeutic strategies targeting SLAMF8, oxidative stress, and mitochondrial dynamics. Such approaches could prove invaluable in managing not only acute COVID-19 but also its long-term sequelae, including "long COVID."
The study findings were published on a preprint server and are currently being peer reviewed for publication into a Nature Journal.
https://www.researchsquare.com/article/rs-5572297/v1
For the latest COVID-19 News, keep on logging to Thailand
Medical News.
Read Also:
https://www.thailandmedical.news/news/russian-study-provides-insights-of-immunothrombosis-in-covid-19
https://www.thailandmedical.news/news/doctors-warn-of-hidden-threat-of-covid-19-involving-portal-vein-thrombosis
https://www.thailandmedical.news/news/how-4g-5g-gene-polymorphisms-influence-covid-19-severity-and-thrombosis-risk
https://www.thailandmedical.news/news/understanding-the-role-of-antibodies-and-complement-in-thrombosis,-a-new-path-to-treatment
Share
Tweet
Share
