How viral toxins exacerbate severe COVID-19

A new study from the University of California, Berkeley, shows that some of the SARS-CoV-2 ‘spike’ proteins shown in the foreground damage the cell barrier lining blood vessels, leading to COVID acute respiratory distress syndrome (ARDS). Including, -19 most dangerous symptoms. (National Institutes of Health photo via Flickr)

Investigation Published today in the journal Nature Communications We reveal how the viral toxin produced by the SARS-CoV-2 virus contributes to severe COVID-19 infection.

This study shows how some of the SARS-CoV-2 ‘spike’ proteins contribute to what is known as vascular leakage by damaging the cell barriers lining blood vessels in body organs such as the lungs. Blocking the activity of this protein may prevent some of the deadliest symptoms of COVID-19, including pulmonary edema, which contributes to acute respiratory distress syndrome (ARDS). there is.

“Theoretically, by specifically targeting this pathway, we could block pathogenesis leading to vascular disease and acute respiratory distress syndrome without having to target the virus itself,” says University of California, Berkeley. said lead author of the study, Scott Biering, a postdoctoral fellow at the school. “Given all the different subspecies emerging and the difficulty of preventing infections from each individually, it is important to focus on the triggers of these etiologies in addition to completely blocking infections.” may be beneficial.”

While many vaccine skeptics have fueled concerns about the potential dangers of the SARS-CoV-2 spike protein, the target of the COVID-19 mRNA vaccine, researchers say their study suggests that the spike protein It said it provided no evidence that it could cause symptoms in its absence. of viral infection. Instead, their research suggests that the spike protein may work in concert with the virus and the body’s own immune response to cause life-threatening symptoms.

Additionally, the amount of spike protein circulating in the body after vaccination is much lower than that observed in severe COVID-19 patients and used in studies.

“At the amount of spike protein in the vaccine, it never causes leakage,” said Eva Harris, senior author of the study and professor of infectious diseases and vaccinology at the University of California, Berkeley. “Furthermore, there is no evidence of that. [the spike protein] itself pathogenic. The idea is that it can help and encourage ongoing infections. “

By examining the effects of the SARS-CoV-2 spike protein on human lung cells and blood vessel cells, as well as on mouse lungs, the research team identified the molecular pathways that enable 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 leakage may be useful for other emerging infectious diseases. may shed light on the pathology behind .

“We believe that many viruses that cause severe disease may encode viral toxins,” Biering said. “These proteins interact with barrier cells independently of viral infection, causing dysfunction of these barriers. Using the principles we learned from the SARS-CoV-2 virus, we hope to find ways to block this etiology so we can be better prepared when the next pandemic strikes.”

How spike proteins cause vascular leakage

Vascular leakage occurs when the cells lining blood vessels and capillaries are destroyed, causing plasma and other fluids to leak out of the bloodstream. In addition to causing the lung and heart damage observed in severe COVID-19, vascular leakage can also lead to hypovolemic shock, the leading cause of death from dengue fever.

Prior to the COVID-19 pandemic, Biering and other members Harris Research Program We were studying the role of the dengue virus protein NS1 in causing vascular leakage and contributing to hypovolemic shock. I thought that it might also contribute to the acute respiratory distress syndrome that led to the death of

Vascular leakage in mouse lungs. Imaged with tracer dye. The top image shows the lung of a healthy mouse and the bottom image shows the lung of a mouse exposed to spike protein. Colors at the red and orange ends of the spectrum correspond to greater vascular leakage. (Image credit: Felix Pahmeier)

“People are aware of the role of bacterial toxins, but the concept of viral toxins is still a really new idea.” We confirmed that it can break down the internal barrier, so we wondered if a spike-like SARS-CoV-2 protein could do the same.”

The spike protein coats the outer surface of SARS-CoV-2 and gives the virus a knobby appearance. They play an important role in helping viruses infect their hosts. The spike protein binds to a receptor called ACE2 on human and other mammalian cells, allowing the virus to enter the cell and hijack cellular function, like a lock turning a lock. When the CoV-2 virus infects cells, it releases most of the spike protein containing the receptor binding domain (RBD).

“What’s really interesting is that the circulating spike protein correlates with severe COVID-19 cases in clinics,” said Biering. “We wanted to ask whether this protein also contributes to the vascular leakage seen in the SARS-CoV-2 setting.”

Scientists now believe that severe COVID-19-related heart and lung damage is due to an exaggerated immune response called cytokine storm. To test the theory that spike proteins may also play a role, Biering and other team members used thin layers of human endothelial and epithelial cells to mimic the lining of blood vessels in the body. They found that exposing these cell layers to spike proteins increased permeability, a hallmark of vascular leakage.

Using CRISPR-Cas9 gene-editing technology, the team showed that this increased permeability also occurred in cells that did not express the ACE2 receptor, indicating that it could occur independently of viral infection. I was. Furthermore, although mice do not express the human ACE2 receptor and cannot be infected with SARS-CoV-2, they found that mice exposed to the spike protein also exhibited vascular leakage.

Finally, with the help of RNA sequencing, researchers found that spike protein causes vascular leakage through a molecular signaling pathway involving glycans, integrins, and transforming growth factor-beta (TGF-beta). did. By blocking integrin activity, the team was able to reverse vascular leakage in mice.

“We have identified a novel virulence mechanism for SARS-CoV-2, in which the spike protein may disrupt the barrier lining the vasculature. Severe cases of COVID-19. Permeability can lead to consequent vascular leakage, as commonly observed in the murine models that can recapitulate the symptoms of these diseases, as commonly observed in the School of Public Health, University of California, Berkeley. “It was interesting to see the similarities and differences between the spike and the dengue virus protein NS1. Both can disrupt the endothelial barrier, but the timelines and host pathways involved seem to differ between the two.” .”

Blocking integrin activity could be a promising target for treating severe COVID-19, but Harris said understanding the precise role of this pathway in disease progression would require He said more research needs to be done. Increased vascular permeability can accelerate infection and lead to internal bleeding, but it also helps the body fight off viruses by improving the immune system’s access to infected cells.

“SARS-CoV-2 evolved to have a spike surface protein with an enhanced ability to interact with host cell membrane factors such as integrins by acquiring the RGD motif. It’s a common integrin-binding factor that many pathogens, including other viruses, use to infect host cells,” said Francielle Tramontini Gomes, former assistant project scientist in the Harris lab and co-first author of the study. says de Sousa. “Our study shows how spike RGD interacts with integrins, leading to TGF-β release and activation of her TGF-β signaling. in vitro When live Understanding the cellular mechanisms of elevated TGF-β levels in COVID-19 patients and how spike-host cell interactions contribute to disease using models of epithelial, endothelial, and vascular permeability I was able to deepen ”

The team continues to study the molecular mechanisms that lead to vascular leakage, and is also investigating viral toxins from other viruses that can cause serious illness in humans.

“COVID-19 is not gone. We have better vaccines now, but we don’t know how the virus will mutate in the future,” Biering said. It may help develop an arsenal of new drugs so that if someone is experiencing vascular leakage it can be targeted. , we can stop that person from dying.”

Other co-authors of this study include Laurentia V. Tjang, Chi Zhu, Richard Ruan, Sophie F. Blanc, Trishna S. Patel, Bryan Castle-Rojas, Nicholas TN Lo, Marcus P. Wong, Colin M. Warnes, Includes Douglas M. His Fox, Anders M. Near, Sarah A. Stanley, and P. Robert Beatty at the University of California, Berkeley. Caroline M. Worthington and John E. Pak of the Chan Zuckerberg Biohub. Dustin R. Glasner, Venice Napkins, Yale A. Santos, Charles Y. Chiu, University of California, San Francisco. Daniel R. Sandoval, Thomas Mandel Clausen, Jeffrey D. Esko. Victoria Ortega and Hector C. Aguilar of Cornell University. Ralph S. Baric of the University of North Carolina at Chapel Hill.

This work was supported by express grants from the National Institute of Allergy and Infectious Diseases (NIAID) (Grants R01 AI24493 and R21 AI146464 Supplementary) and Emergency Ventures. Additional support is provided by the National Science Foundation (grant RAPID 201989), the National Heart, Lung, and Blood Institute (NHLBI) (grant HL131474), the National Institutes of Health (R01 AI109022), the Institute for Innovative Genomics, Life Sciences. provided. research foundation.

Related information