Salk researchers and collaborators show how the protein damages cells
By SALK INSTITUTE
Scientists have known for a while that SARS-CoV-2’s distinctive “spike” proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that they also play a key role in the disease itself.
The
paper, published on April 30, 2021, in Circulation Research,
also shows conclusively that COVID-19 is a vascular disease, demonstrating
exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a
cellular level. The findings help explain COVID-19’s wide variety of seemingly
unconnected complications, and could open the door for new research into more
effective therapies.
“A lot of people think of it as a respiratory disease, but it’s really a vascular disease,” says Assistant Research Professor Uri Manor, who is co-senior author of the study.
“That could explain why some people have strokes, and why some
people have issues in other parts of the body. The commonality between them is
that they all have vascular underpinnings.”
Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.
While the findings themselves aren’t entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time.
There’s been a growing
consensus that SARS-CoV-2 affects the vascular system, but exactly how it did
so was not understood. Similarly, scientists studying other coronaviruses have
long suspected that the spike protein contributed to damaging 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
SARS-CoV-2 classic crown of spike proteins, but did not contain any actual
virus. Exposure to this pseudovirus resulted in damage to the lungs and
arteries of an animal model—proving that the spike protein alone was enough to
cause disease. Tissue samples showed inflammation in endothelial cells lining
the pulmonary artery walls.
The
team then replicated this process in the lab, exposing healthy endothelial
cells (which line arteries) to the spike protein. They showed that the spike
protein damaged the cells by binding ACE2. This binding disrupted ACE2’s
molecular signaling to mitochondria (organelles that generate energy for
cells), causing the mitochondria to become damaged and fragmented.
Previous
studies have shown a similar effect when cells were exposed to the SARS-CoV-2
virus, but this is the first study to show that the damage occurs when cells
are exposed to the spike protein on its own.
“If
you remove the replicating capabilities of the virus, it still has a major
damaging effect on the vascular cells, simply by virtue 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 insight towards the infectivity and severity of mutant SARS CoV-2 viruses.”
The
researchers next hope to take a closer look at the mechanism by which the
disrupted ACE2 protein damages mitochondria and causes them to change shape.
Reference:
“SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of
ACE 2” by Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui
Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerald S. Shadel,
Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul
Malhotra, Uri Manor, Shengpeng Wang, Zu-Yi Yuan and John Y-J. Shyy, 31 March
2021, Circulation Research.
DOI:
10.1161/CIRCRESAHA.121.318902
The research was supported by the National Institutes of Health, the National Natural Science Foundation of China, the Shaanxi Natural Science Fund, the National Key Research and Development Program, the First Affiliated Hospital of Xi’an Jiaotong University; and Xi’an Jiaotong University.