Mutation in SARS-CoV-2 ramps up ability to infect cells, makes it more stable: Scripps study

The number, or density, of spikes on the mutated virus is 4 or 5 times greater, making it more infectious.


A variant of the SARS-CoV-2 virus, which is responsible for the still-raging coronavirus pandemic sweeping the world, has been found in multiple studies to have a very tiny mutation in its genetic code. This variant is primarily circulating through Europe and the United States, according to a study released by Scripps Research, and the genetic tweak significantly increases the virus’ ability to infect cells in a host.

"Viruses with this mutation were much more infectious than those without the mutation in the cell culture system we used," virologist Hyeryun Choe, senior author of the study, said in a statement.

The researchers argue that the mutation caused a marked increase in the number of spikes on the viral surface. The spikes are a very important part of the virus' architecture – it allows the virus to bind to cells and enter them, starting the process of infection.

"The number — or density — of functional spikes on the virus is 4 or 5 times greater due to this mutation,” Choe said.

The spikes, which are easily the most noticeable feature of the coronavirus in its now-popular illustrations, give it a crown-like appearance. They also give the virus its ability to latch onto a cell through specific receptors that it attaches to – the ACE2 receptors.

In the mutant virus, the "D614G" mutation [where the amino acid at position 614 is changed from aspartic acid (D), to glycine (G)] gives these spikes more flexibility in their "backbone", co-author of the study Michael Farzan, co-chairman of the Scripps Research Department of Immunology and Microbiology, said in the statement.

An illustration of the 2019 Novel Coronavirus (2019-nCoV), which was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China and now a raging global pandemic. Image: CDC

An illustration of the 2019 Novel Coronavirus (2019-nCoV), which was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China and now a raging global pandemic. Image: CDC

More flexible spikes mean that the mutated virus is less likely to fall apart or disintegrate when it makes it way from an infected cell to a healthy target cell, he explains.

"Our data are very clear – the virus becomes much more stable with the mutation," Choe adds.

The study offers some evidence to back a theory that has been making the rounds in scientific circles for a while now – that there is an explanation for why the COVID-19 outbreaks in Italy and New York were much more overwhelming on health systems compared to elsewhere in the world. Early outbreaks in San Francisco and Washington were more "readily managed" – at least initially. But many questions and theories have surfaced about whether the virus had changed or become more virulent and dangerous in later cases, where community transmission was involved.

It is widely-known that viruses tend to acquire small genetic changes as they reproduce and spread. These changes rarely affect the virus's fitness or ability to compete (with the hosts, in this case, humans) for survival.

The SARS-CoV-2 variant that made the rounds during the earliest regional outbreaks didn't have the D614G mutation that is reportedly dominating some of the worst-affected regions in the world today.

Their research was carried out using a harmless, re-engineered virus that makes all the key proteins that the coronavirus does. The changes that were seen in this re-engineered virus still need to be studied in the context of epidemiology – to see how these findings translate to transmission and infection rate in the real world, where there are many more variables at play.

The structure and cross-sectional view of Human Coronavirus. It shows depicting the shape of coronavirus as well as the cross-sectional view. Image shows the major elements including the Spike S protein, HE protein, viral envelope, and helical RNA. Image credit: Wikipedia

The structure and cross-sectional view of the novel coronavirus. Image shows the major elements including the Spike S protein, HE protein, viral envelope, and helical RNA. Image credit: Wikipedia

Choe and Farzan, who have been studying coronaviruses for nearly 20 years – since the first outbreak of SARS, were the first to discover that SARS bound to the ACE2 receptor on cells. More recent studies by other scientists have shown that the COVID- causing SARS-CoV-2 virus also binds to the same ACE2 receptor.

The duo has found an important difference between the spike proteins in the SARS virus and the new pandemic strain SARS-CoV-2. Both viruses, under an electron microscope, show that the spike has tripod shape. But, in SARS-CoV-2, the tripod is divided in two discreet segments – S1 and S2 – unlike in the SARS virus. This unusual feature produced unstable spikes, Farzan says.

Just one in every four of the several hundred spikes on every SARS-CoV-2 virus has the stable structure needed to successfully infect a host cell, according to Farzan. The D614G mutation lends some strength to the tripod structure, which breaks much less frequently – meaning more of its spikes are fully functional, the study reports.

According to the researchers, evidence of how quickly the mutated virus has spread can be seen in the sequence data from different strains that scientists have contributed to global databases like GenBank. In February 2020, there were no sequences deposited to the GenBank database showing the D614G mutation. By March, it appeared in roughly 1 out of every 4 collected samples. By May, it could be seen in 70 percent of all the samples collected, Farzan says.

"Over time, it has figured out how to hold on better and not fall apart until it needs to," Farzan says. "The virus has, under selection pressure, made itself more stable."

A vaccine candidate against COVID-19 (the SARS-CoV-2 virus), provided by Imperial College London. About a dozen vaccine candidates are in early stages of testing in thousands of people. Image: Imperial College London via AP

A vaccine candidate against COVID-19 (the SARS-CoV-2 virus), provided by Imperial College London. About a dozen vaccine candidates are in early stages of testing in thousands of people. Image: Imperial College London via AP

There is still quite a bit of information about the new variant of SARS-CoV-2 that is unknown – for instance, whether this small change affects the severity of symptoms in people it infects, and how it affects mortality, the researchers said. Much more data, ideally under controlled studies, are needed, Choe says.

If there's one silver lining in this discovery, it would be that the immune factors from the serum of infected people worked equally well against viruses with and without the D614G mutation in their study. So, vaccine candidates already in development could likely work against both variants, according to Choe.

Currently undergoing peer review, the research paper is has been posted prior to publication in the pre-print server bioRxiv.


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