In a new study, University of California, Berkeley researchers find that portions of the SARS-CoV-2 “spike” protein, shown in the foreground, can damage the cellular barriers lining the inside of blood vessels , which contributes to some of the COVID cases. -19 of the most dangerous symptoms, including acute respiratory distress syndrome (ARDS). (Photo from the National Institutes of Health via Flickr)
A study published today in the journal Nature Communications reveals how a viral toxin produced by the SARS-CoV-2 virus may contribute to severe COVID-19 infections.
The study shows how a portion of the SARS-CoV-2 “spike” protein can damage the cellular barriers that line the inside of blood vessels within body organs, such as the lungs, contributing to what is known as vascular leak. Blocking the activity of this protein can help prevent some of the deadliest symptoms of COVID-19, including pulmonary edema, which contributes to acute respiratory distress syndrome (ARDS).
“In theory, by specifically targeting this pathway, we could block the pathogenesis that leads to vascular disorder and ARDS without needing to target the virus itself,” said study lead author Scott Biering, a postdoctoral fellow. at the University of California, Berkeley. . “In light of all the different variants that are emerging and the difficulty of preventing infection from each one individually, it might be beneficial to target these pathogenesis triggers in addition to blocking infection entirely.”
While many vaccine skeptics have raised fears about the potential dangers of the SARS-CoV-2 spike protein, which is the target of COVID-19 mRNA vaccines, the researchers say their work provides no evidence that the spike protein can cause symptoms in absentia. of viral infection. Instead, their study suggests that the spike protein may work in concert with the virus and the body’s own immune response to trigger life-threatening symptoms.
Furthermore, the amount of spike protein circulating in the body after vaccination is much less concentrated than the amounts that were seen in patients with severe COVID-19 and used in the study.
“The amount of spike protein you would have in a vaccine could never cause a leak,” said the study’s lead author, Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley. Furthermore, there is no evidence that [the spike protein] it is pathogenic by itself. The idea is that it can aid and abet an ongoing infection.”
By examining the impact of the SARS-CoV-2 spike protein on human lung and vascular cells, and in the lungs of mice, the research team was able to discover the molecular pathways that allow the spike protein to break barriers. critical internals of the body. . In addition to opening new avenues for the treatment of severe COVID-19, understanding how the spike protein contributes to vascular leakage could shed light on the pathology behind other emerging infectious diseases.
“We think that many viruses that cause severe disease can 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 spread, and amplification of the virus and vascular leakage is what triggers severe disease. I hope we can use the principles we have learned from the SARS-CoV-2 virus to find ways to block this pathogenesis so that we are more prepared when the next pandemic strikes.”
How the spike protein triggers vascular leakage
Vascular leakage occurs when cells lining blood vessels and capillaries rupture, allowing plasma and other fluids to leak out of the bloodstream. In addition to causing the lung and heart damage seen in severe cases of COVID-19, vascular leak can also lead to hypovolemic shock, the leading cause of death from dengue.
Prior to the COVID-19 pandemic, Biering and other members of the Harris Research Program were studying the role of the dengue virus NS1 protein in triggering vascular leakage and contributing to hypovolemic shock. When the pandemic hit, the team wondered if a similar viral toxin in SARS-CoV-2 might also be contributing to the acute respiratory distress syndrome that was killing COVID-19 patients.
Vascular leak in the lungs of mice, photographed with tracer dye. The top image shows a healthy mouse lung and the bottom image is a mouse lung that has been exposed to the spike protein. Colors at the red and orange end of the spectrum correspond to increased vascular leakage. (Image courtesy of Felix Pahmeier)
“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 by dengue virus-infected cells that, even in the absence of the virus, can cause endothelial permeability and break down internal barriers. So we wondered if a SARS-CoV-2 protein, like Spike, could do similar things.”
Spike proteins cover 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 opening a lock, allows the virus to enter the cell and hijack cellular function. The SARS-CoV-2 virus sheds a large part of the receptor-binding domain (RBD)-containing spike protein when it infects a cell.
“What’s really interesting is that circulating spike protein correlates with severe cases of COVID-19 in the clinic,” Biering said. “We wanted to ask if this protein also contributed to any vascular leakage that we saw in the context of SARS-CoV-2.”
Scientists now 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 cell layers to the spike protein increased their permeability, a hallmark of vascular leakage.
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. Furthermore, they found that mice that were exposed to the spike protein also exhibited vascular leakage, despite the fact that the mice do not express the human ACE2 receptor and cannot be infected with SARS-CoV-2.
Finally, with the help of RNA sequencing, the researchers found that the spike protein triggers vascular leakage through a molecular signaling pathway that involves glycans, integrins, and transforming growth factor-beta (TGF-beta). By blocking the activity of the integrins, the team was able to reverse vascular leakage in mice.
“We identified a new pathogenic mechanism of SARS-CoV-2 in which the spike protein can break the barriers that line our vasculature. The resulting increase in permeability can lead to vascular leakage, as is commonly seen in severe cases of COVID-19, and we could recapitulate those disease manifestations in our mouse models,” said study co-author Felix Pahmeier, a student Graduate in the lab of Harris. at the UC Berkeley School of Public Health. “It was interesting to see the similarities and differences between Spike and the dengue virus NS1 protein. Both are capable of disrupting endothelial barriers, but the timelines and host pathways involved appear to differ between the two.”
While blocking integrin activity may be a promising target for treating severe COVID-19, Harris said more work is needed to understand the exact role of this pathway in disease progression. While increased vascular permeability can speed up infection and lead to internal bleeding, it can also help the body fight the virus by giving the immune machinery better access to infected cells.
“SARS-CoV-2 evolved to have a spike surface protein with greater ability to interact with host cell membrane factors, such as integrins, by acquiring an RGD motif. This motif is a common integrin-binding factor exploited by many pathogens, including bacteria and other viruses, to infect host cells,” said Francielle Tramontini Gomes de Sousa, a former project scientist in Harris’ lab and co-first author of the study. . “Our study shows how Spike RGD interacts with integrins, resulting in the release of TGF-beta and the activation of TGF-beta signalling. Using in vitro and in vivo models of epithelial, endothelial, and vascular permeability, we were able to improve understanding of the cellular mechanisms of increased TGF-beta levels in COVID-19 patients and how host cell-spike interactions might contribute to the disease.
The team continues to study the molecular mechanisms that lead to vascular leakage and is also investigating possible viral toxins in other viruses that cause severe disease in humans.
“COVID-19 has not gone away. We have better vaccines now, but we don’t know how the virus is going to mutate in the future,” Biering said. “Studying this process can help us develop a new arsenal of drugs so that if someone experiences a vascular leak, we can target that. It may not stop the replication of the virus, but it could prevent that person from dying.”
Other coauthors of this study are Laurentia V. Tjang, Chi Zhu, Richard Ruan, Sophie F. Blanc, Trishna S. Patel, Bryan Castillo-Rojas, Nicholas TN Lo, Marcus P. Wong, Colin M. Warnes, Douglas M Fox, Anders M. Näär, Sarah A. Stanley, and P. Robert Beatty of UC Berkeley; Caroline M. Worthington and John E. Pak of the Chan Zuckerberg Biohub; Dustin R. Glasner, Venice Servellita, Yale A. Santos, and Charles Y. Chiu of the University of California, San Francisco; Daniel R. Sandoval, Thomas Mandel Clausen, and Jeffrey D. Esko of the University of California, San Diego; Victoria Ortega and Hector C. Aguilar of Cornell University; and Ralph S. Baric of the University of North Carolina at Chapel Hill.
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (grants R01 AI24493 and R21 AI146464 Supplement) and a rapid grant from Emergent Ventures. The National Science Foundation (RAPID grant 201989), the National Heart, Lung, and Blood Institute (NHLBI) (grant HL131474), the National Institutes of Health (R01 AI109022), the Institute for Innovative Genomics, and Life Sciences provided support. additional. Research Foundation.
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