The various ways in which COVID-19 affects the body has made it difficult to find effective treatments, but now scientists think they've figured out why - it's actually a vascular disease.
That's one which primarily affects blood vessels, in particular endothelial cells, which line the vessels' interior.
"A lot of people think of it as a respiratory disease, but it's really a vascular disease," said Uri Manor, co-author of a new study into how COVID-19 attacks the body. "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."
When it first appeared in late 2019, the mysterious illness was believed to be a respiratory illness. It's even in the name of the virus itself - SARS-CoV-2 short for 'severe acute respiratory syndrome coronavirus 2', the first being behind the 2002/3 disease that was quickly snuffed out.
But in the 16 months since it was first reported to the World Health Organization, it's become clear COVID-19 - the name given to the disease caused by SARS-CoV-2 - is much more than that. The virus can cause damage to "nearly every organ system in the body", researchers in the US said in a recent study, with the potential long-term effects far worse than those of influenza.
The latest study, carried out at the Salk Institute for Biological Studies in San Diego, involved pumping copies of a 'pseudovirus' into hamsters. The fake virus had no actual viral genetic material, but was surrounded by the virus' spike protein - the pointy bits you see in pictures.
Even without any virus, the pseudovirus caused damage to the animals' lungs and arteries - proving the spike protein itself was harmful. When the hamsters' endothelial cells were exposed to the pseudovirus, they also caused serious damage - binding to a receptor on the cells called ACE2 and hindering the cells' ability to generate energy, causing them to "become damaged and fragmented".
"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," said Prof Manor.
Science communicator Alison Campbell, an honorary fellow at the University of Waikato, told Newshub ACE2 receptors are "common in many tissues", including cells lining our blood vessels and lungs.
"We already knew that the virus does a lot of damage via its 'life cycle', because cells are damaged/destroyed when the new virus particles burst out of the cells where they were made. What this paper appears to show is that the spike protein itself can cause damage to those endothelial cells, doing this by lowering the production of the ACE2 protein and interfering with the cell's mitochondria."
The two most successful vaccines against COVID-19 to date - those made by Moderna and Pfizer/BioNTech - work by getting the body to produce copies of the spike protein, teaching the immune system what it looks like. But if the spike protein itself can cause problems, is that a problem?
Voices for Freedom, a New Zealand group which spreads misinformation and misleading claims about COVID-19 and vaccines, said the research "begs the question: if this new manufactured virus-free spike protein can do damage like this, what does this mean for the walking spike protein factories we are creating with certain products?"
But scientists don't think so. Vaccinologist Helen Petousis-Harris, director of the University of Auckland's Vaccine Datalink and Research Group, told Newshub spike proteins created by our body after being vaccinated aren't presented to other cells.
"While the body makes the spike protein, it doesn't release them - the spike proteins are made inside some cells, and then they're broken down into fragments [which are] displayed on the outside of the cell."
These fragments are enough for the immune system to build up its defences, so if it ever sees them on a real SARS-CoV-2 spike protein, it knows it's an enemy.
"When a vaccinated cell reaches the end of its life, the proteins and fragments are snaffled up by immune cells, along with the other cellular debris," said Dr Campbell. This happens after a couple of days.
Even if the spike protein was presented in full, she says it's unlikely it would cause any problems - vaccines go into the muscle tissue, not the bloodstream.
"It seems highly improbable that vaccination would result in a massive flood of spike proteins into the vascular system," said Dr Campbell.
"People often imagine the components of vaccines charging around the body via the bloodstream - but that is not actually what happens," said Dr Petousis-Harris.
"When the injection is given, into the muscle of the arm, not the blood, the cells in the area as well as specialised immune cells basically inhale the vaccine material. The spike protein is produced in these cells and it actually gets broken down into bits in the same cells. These bits get coupled to special molecules and then the who package is presented to the immune system. There is no rush of spike proteins.
"If the vaccine caused vascular disease we would have seen evidence of this after the hundreds of millions of doses of RNA vaccines already given. This is not something we need to be worried about from a vaccine perspective - vaccines will prevent this from happening."
There is also no evidence of the vaccine causing vascular illness, said Dr Petousis-Harris, after more than a billion doses.
"So first of all biologically this seems unlikely, and two, the evidence would argue against that."