SARS-CoV-2 Pops Up, Mutated, Beyond the Respiratory Tract

As if the waves of novel variants of “interest” and “concern” sweeping the planet haven’t been enough, and we find versions of SARS-CoV-2 dodging in and out of species in a complex pattern of spillovers and spillbacks, we discover that it’s even sneakier. Two new papers in Nature Communications, from a group at the Max Planck Bristol Centre of Minimal Biology, describe how the virus can differ genetically in different parts of the same host.

That may mean that if vaccines and treatments vanquish the virus in the respiratory tract, the pathogen might persist elsewhere. And the viruses in new places replicate and infect more vigorously, better able to elude our immune response. That’s not good news as protection from vaccinations or having had COVID-19 wanes.

We already knew that the virus can spew new mutations within the body of a person with compromised immunity. And it mutates rapidly in the non-vaccinated. But the new research shows that novel variants percolate into existence in different bodily niches – with an individual.

“Our results showed that one can have several different virus variants in one’s body. Some of these variants may use kidney or spleen cells as their niche to hide, while the body is busy defending against the dominant virus type. This could make it difficult for the infected patients to get rid of SARS-CoV-2 entirely,” said Kapil Gupta, lead author of one article.

The action of a virus entering a host cell centers around a pocket in the part of the virus’s spike protein that the immune system recognizes. Altering the three-dimensional shape of the pocket makes the virus like the Romulan cloaking device from Star Trek, which makes their warships dissolve into invisibility as a Federation starship nears.

The researchers studied the pocket in viruses from a single English patient that have a deletion mutation that removes 8 of the 1273 amino acids of the spike protein. This happens near a critical spot called the furin cleavage site, which is where the two parts of the spike are cut, one glomming onto a human cell while the other drags the virus inside the cell.

But instead of the missing part disabling the virus, the researchers found that the pathogen contorts so that it can still enter human cells. And that’s part of how it continually reinvents itself, in different ways in different nooks and crannies of a host’s hapless body. The English patient’s version of the virus, called BriSdelta, replicates vigorously in monkey kidney cells in culture and in human colon cancer cells, but not in human lung cancer lining cells. That could mean that the predilection for respiratory surfaces shifts to elsewhere when the virus is impaired.

The new version of the virus is also better at replicating and infecting than earlier variants. “In the heterogeneous environment of the human body, such deletion variants can emerge in suitable cell types serving as potential niches for SARS-CoV-2 to further evolve or specialize,” the researchers write.

Terrific.

The researchers probed how this happens using artificial versions of the virus assembled using synthetic biology techniques. The second paper describes their “synthetic minimal virions,” aka MiniVs, of wild type SARS-CoV-2 and combinations of the mutations that have peppered the parade of variants.

And they found that when fatty acids released during inflammation – the initial innate response to infection – bind the new mutant, a subtle shift in the position of the spike cloaks it from the onslaught of antibodies from the more specific adaptive arm of the immune response.

The researchers have formed a company, Halo Therapeutics, to develop pan-coronavirus antivirals based on the tango between the pocket and the ACE-2 receptors on human cells – no matter where in the body they are.

So as we take off our masks and joyously get back to some semblance of normality, let’s not forget that SARS-CoV-2 is still out there, everywhere, and ever changing. We must be ready for next time – more on that next week.