Thank
you, Dr. Sheri Tenpenny.
The novel coronavirus’ spike
protein plays an additional key role in illness
Salk researchers and collaborators
show how the protein damages cells, confirming COVID-19 as a primarily vascular
disease
LA JOLLA—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 the
virus spike proteins (which behave very differently than those safely encoded
by vaccines) 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.
 |
Representative images of vascular
endothelial control cells (left) and cells treated with the SARS-CoV-2 Spike
protein (right) show that the spike protein causes increased mitochondrial
fragmentation in vascular cells. |
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.
Other authors on the study are Yuyang Lei and Zu-Yi Yuan of
Jiaotong University in Xi’an, China; Cara R. Schiavon, Leonardo Andrade, and
Gerald S. Shadel of Salk; Ming He, Hui Shen, Yichi Zhang, Yoshitake Cho, Mark
Hepokoski, Jason X.-J. Yuan, Atul Malhotra, Jin Zhang of the University of
California San Diego; Lili Chen, Qian Yin, Ting Lei, Hongliang Wang and
Shengpeng Wang of Xi’an Jiatong University Health Science Center in Xi’an,
China.
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.
DOI: 10.1161/CIRCRESAHA.121.318902
