A CCORDING to a recent study published in the journal Nature Communications, the SARS-CoV-2 virus may create a viral toxin that causes severe COVID-19 infections.
The research demonstrates how the SARS-CoV-2 “spike” protein can harm cell barriers that line the interior of blood veins within bodily organs like the lungs, causing what is known as a vascular leak. One of COVID-19’s deadliest symptoms, pulmonary oedema, which contributes to acute respiratory distress syndrome, may be avoided by blocking the function of this protein (ARDS).
Specifically targeting this pathway
“In theory, by specifically targeting this pathway, we could block pathogenesis that leads to vascular disorder and acute respiratory distress syndrome without needing to target the virus itself,” said study lead author Scott Biering, a postdoctoral scholar at the University of California, Berkeley. “In light of all the different variants that are emerging and the difficulty in preventing infection from each one individually, it might be beneficial to focus on these triggers of pathogenesis in addition to blocking infection altogether.”
While many vaccine sceptics have stoked fears about the potential dangers of the SARS-CoV-2 spike protein — which is the target of COVID-19 mRNA vaccines — the researchers say that their work provides no evidence that the spike protein can cause symptoms in the absence of viral infection.
Instead, their study suggests that the spike protein may work in tandem with the virus and the body’s own immune response to trigger life-threatening symptoms.
Patients with severe COVID-19
In addition, the amount of spike protein circulating in the body after vaccination is far less concentrated than the amounts that have been observed in patients with severe COVID-19 and that were used in the study.
“The amount of spike protein that you would have in a vaccine would never be able to cause a leak,” said study senior author Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley. “In addition, there’s no evidence that [the spike protein] is pathogenic by itself. The idea is that it’s able to aid and abet an ongoing infection.”
By examining the impact of the SARS-CoV-2 spike protein on human lung and vascular cells, and on the lungs of mice, the research team was able to uncover the molecular pathways that allow the spike protein to disrupt critical internal barriers in the body. In addition to opening new avenues for the treatment of severe COVID-19, understanding how the spike protein contributes to vascular leak could shed light on the pathology behind other emerging infectious diseases.
A viral toxin
We think that a lot of viruses that cause severe disease may encode a viral toxin,” Biering said. “These proteins, independent of viral infection, interact with barrier cells and cause these barriers to malfunction. This allows the virus to disseminate, and that amplification of the virus and the vascular leak is what triggers the severe disease. I’m hoping that we can use the principles that we’ve learned from the SARS-CoV-2 virus to find ways to block this pathogenesis so that we are more prepared when the next pandemic happens.”
A vascular leak occurs when the cells that line blood vessels and capillaries are disrupted, allowing plasma and other fluids to leak out of the bloodstream. In addition to causing the lung and heart damage observed in severe COVID-19, a vascular leak can also lead to hypovolemic shock, the primary cause of death from dengue.
Harris Research Programme
Before the COVID-19 pandemic, Biering and other members of the Harris Research Programme were studying the role of dengue virus protein NS1 in triggering vascular leaks and contributing to hypovolemic shock. When the pandemic hit, the team wondered if a similar viral toxin in SARS-CoV-2 could also be contributing to the acute respiratory distress syndrome that was killing COVID-19 patients.
“People are aware of the role of bacterial toxins, but the concept of a viral toxin is still a really new idea,” Harris said. “We had identified this protein secreted from dengue virus-infected cells that, even in the absence of the virus, is able to cause endothelial permeability and disrupt internal barriers. So, we wondered if a SARS-CoV-2 protein, like a spike, might be able to do similar things.”
Spike proteins coat the outer surface of SARS-CoV-2, giving the virus its knobby appearance. They play a critical role in helping the virus infect its hosts: The spike protein binds to a receptor called ACE2 on human and other mammalian cells, which — like a key turning a lock — allows the virus to enter the cell and hijack cellular function. The SARS-CoV-2 virus sheds a large portion of the spike protein containing the receptor-binding domain (RBD) when it infects a cell.
Protein correlates
“What’s really interesting is that circulating spike protein correlates with severe COVID-19 cases in the clinic,” Biering said. “We wanted to ask if this protein was also contributing to any vascular leak we saw in the context of SARS-CoV-2.”
Currently, scientists attribute the heart and lung damage associated with severe COVID-19 to an overactive immune response called a cytokine storm. To test the theory that the spike protein might also play a role, Biering and other team members used thin layers of human endothelial and epithelial cells to mimic the linings of blood vessels in the body. They found that exposing these cellular layers to the spike protein increased their permeability, a hallmark of the vascular leak.
Using CRISPR-Cas9 gene editing technology, the team showed that this increased permeability occurred even in cells that did not express the ACE2 receptor, indicating that it could occur independently of viral infection. In addition, they found that mice that were exposed to the spike protein also exhibited vascular leak, even though mice do not express the human ACE2 receptor and cannot be infected with SARS-CoV-2. SOURCE: ANI
