Sometimes, scientists have to do things that make them sound … well, a bit like an evil movie villain. Like, say you wanted to work out the pathology and mechanism of a novel virus that’s killed millions across the planet – the best way to do that would involve purposefully infecting a bunch of people with said virus. Or maybe you want to figure out how the virus is going to evolve over time, so you, um, give it new mutations yourself and see which ones it likes.
But as maniacal as those research projects sound on paper, they were done for a really good reason: to give us new and better knowledge to fight the coronavirus pandemic. And a new study, published in the journal Nature Communications, fits exactly into this niche: researchers from Germany and the UK created a synthetic COVID-19 virus from scratch – and discovered something incredibly important about how the virus evades our bodies’ immune systems.
“Using this technique to study the spike protein … [the researchers] discovered a switching mechanism,” explains a statement from the Max Planck Institute for Medical Research, where the research was carried out.
“Upon binding of inflammatory fatty acids, the spike protein changes its conformation, thereby becoming less ‘visible’ to the hosts immune system.”
Studying COVID-19 in the lab comes with quite a few challenges, not least of which is the potential for researchers themselves to get infected. It can also be difficult to study individual mechanisms of the natural virus – as the team behind the new study were aiming to do – rather than the entire infection as a whole.
So, instead, the team used something called “bottom-up synthetic biology” – they built synthetic SARS-CoV-2 virus particles, or virions. These had a similar structure to real SARS-CoV-2 virus particles, but contained no genetic information, meaning there was no danger to the researchers of getting infected.
“Even more important for us, as we build these synthetic virions from scratch, is that we can precisely design their composition and structure,” explained first author Oskar Staufer. “This allows us to perform a very systematic, step-by-step study on distinct mechanisms.”
The team had shown in a previous study that the infamous COVID-19 spike protein contained something called a fatty acid binding pocket – an area on the spike particularly susceptible to a certain type of immune molecule. But what they didn’t know was why – after all, the SARS-CoV-2 virus is notorious for evolving around immune responses, so why would it still have this pocket of vulnerability after more than two years?
Thanks to the virions, we now know the answer. It seems the SARS-CoV-2 particles may be using our bodies’ immune response for their own benefit: when a fatty acid immune molecule binds with this pocket, the researchers discovered, the spike protein "folds" down.
This means it can’t infect the host cells anymore – but it also means that host antibodies are less able to bind to it. You can think of it kind of like folding down a switchblade: sure, you can’t stab any Sharks or Jets [delete as appropriate] with it, but it’s way less likely Sergeant Krupke is going to notice you have a weapon and arrest you this way.
“By ‘ducking down’ … the spike protein upon binding of inflammatory fatty acids, the virus becomes less visible to the immune system,” said Staufer. “This could be a mechanism to avoid detection by the host and a strong immune response for a longer period of time and increase total infection efficiency.”
While the discovery is pretty amazing, it’s just the beginning of what the team think is possible with their synthetic COVID-19 virus tech. The next step will be to figure out exactly why the virus uses this “ducking” mechanism – and whether we can exploit it for future treatments or vaccines.
“Applying such synthetic biology concepts to a problem with global impact is truly exciting,” said Staufer.