Scientists have known for some time that the distinctive SARS-CoV-2 “spike” proteins help the virus infect its host by attaching to healthy cells. Now, a major new study shows that they also play a key role in the disease itself.
The article, published on April 30, 2021, in Traffic Research, also conclusively shows that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system at the cellular level. The findings help explain the wide variety of seemingly unrelated complications from COVID-19 and may open the door to further research into more effective therapies.
“A lot of people think of it as a respiratory disease, but it’s really a vascular disease,” says research assistant professor Uri Manor, co-lead author of the study. “This could explain why some people have strokes and why some people have problems in other parts of the body. The common thread between them is that they all have vascular foundations.”
Salk researchers collaborated with scientists at the University of California at San Diego on the article, including co-first author Jiao Zhang and co-lead author John Shyy, among others.
Although the results themselves are not entirely a surprise, the article provides clear confirmation and a detailed explanation of the mechanism by which the protein damages vascular cells for the first time. There is a growing consensus that SARS-CoV-2 affects the vascular system, but it is not clear exactly how it did. Likewise, scientists studying other coronaviruses have long suspected that the spike protein has helped damage vascular endothelial cells, but this is the first time the process has been documented.
In the new study, the researchers created a “pseudovirus” that was surrounded by the classic SARS-CoV-2 crown of spike proteins, but contained no real viruses. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model – proving that the spike protein alone was sufficient to cause disease. The tissue samples showed inflammation of the endothelial cells lining the walls of the pulmonary arteries.
The team then replicated this process in the lab, exposing healthy endothelial cells (which line the arteries) to the spike protein. They showed that the spike protein damaged cells by binding to ACE2. This binding disrupted the molecular signaling of ACE2 to mitochondria (organelles that generate energy for cells), causing damage and fragmentation of mitochondria.
Previous studies have shown a similar effect when cells are exposed to the SARS-CoV-2 virus, but this is the first study to show that damage occurs when cells are exposed to the spike protein alone.
“If you suppress the virus’s replication capabilities, it still has a major detrimental effect on vascular cells, simply because of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID” , Manor explains. . “Further studies with mutant spike proteins will also provide new information on the infectivity and severity of mutant SARS CoV-2 viruses.”
The researchers then hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.
The other authors of the study are Yuyang Lei and Zu-Yi Yuan from Jiaotong University in Xi’an, China; Cara R. Schiavon, Leonardo Andrade and Gerald S. Shadel de Salk; Ming He, Hui Shen, Yichi Zhang, Yoshitake Cho, Mark Hepokoski, Jason X.-J. Yuan, Atul Malhotra, Jin Zhang of the University of California at San Diego; Lili Chen, Qian Yin, Ting Lei, Hongliang Wang, and Shengpeng Wang from Xi’an Jiatong University Health Sciences Center in Xi’an, China.
The research was supported by National Institutes of Health, National Natural Science Foundation of China, Shaanxi Natural Science Fund, National Key Research and Development Program, Xi University’s first affiliated hospital. an Jiaotong; and Xi’an Jiaotong University.