What Makes Covid-19 Severe? Study Uncovers Role Of Virus Proteins Other Than Spike

The genes on the novel coronavirus contribute to how fiercely the body responds to a Covid-19 infection by controlling the immune system of the host. 

The spike protein of SARS-CoV-2, the causative organism of Covid-19, plays a vital role in the process of virus invasion by binding to the host cell receptor and inducing virus-cell membrane fusion. Now, a new study has uncovered the role of proteins of SARS-CoV-2, or novel coronavirus, other than the spike protein. Researchers at the University of Maryland School of Medicine have identified how multiple genes of SARS-CoV-2 affect the severity of Covid-19. More knowledge about these genes could lead to new ways of developing future vaccines or treatments. 

The genes on the novel coronavirus contribute to how fiercely the body responds to a Covid-19 infection by controlling the immune system of the host. 

People usually visualise the spike protein as the structural "crown" that acts as the driving factor behind each new variant of Covid-19. However, the new study published recently in the Proceedings of the National Academy of Sciences, showed that mutations in other "accessory" genes also play a role in how the disease progresses. Researchers believe that accessory proteins need to be studied further because their mutations may increasingly become more significant as newer variants arise.

The BA.5 variant of Omicron has overtaken the BA.4 variant of the virus, and is circulating the Earth now. Both BA.4 and BA.5 elude the immune system because of mutations in the spike protein. Researchers believe that previous Covid-19 vaccines are not as effective in preventing disease due to the spike mutations. 

What are the three kinds of genes on SARS-CoV-2?

The novel coronavirus has three kinds of genes. One of them is involved in making more copies of the virus, another one makes the virus structure, and the other kind includes the accessory genes, which have other functions. The aim of the new study was to find out the function of the accessory genes. 

The researchers recreated viruses missing each of four accessory proteins and then infected mice with these new viruses or the original virus, in order to find out the function of the accessory gene. Then, the researchers observed how each virus affected the mice. 

Do non-spike protein genes affect disease severity?

In a statement released by University of Maryland School of Medicine, Dr Matthew Frieman, one of the authors on the paper, said both BA.4 and BA.5 variants have the same genetic sequence for the spike protein, implying that it is the other genes — the non-spike protein genes — that seem to affect the way SARS-CoV-2 copies itself and causes disease. Therefore, mutations in these other accessory genes are likely to have allowed variants like BA.5 to outcompete the earlier versions of the virus. 

What role does ORF3a/b gene play in disease severity?

According to the statement, Dr Frieman's team of researchers found that viruses missing the ORF3a/b gene led to milder infections than the original SARS-CoV-2, and the mice with this virus strain lost less weight and had less virus in their lungs than mice infected with the original virus. The researchers concluded that the ORF3a/b gene likely plays a role in either making copies of the virus through viral replication or blocking the immune response to the infection. 

According to the study, some experiments suggested that ORF3a/b seemingly activates the body's innate immune system, the first line of defence launched by the immune system. In this way, the gene signals to the immune system that a foreign invader needs to be vanquished.

What role does the ORF8 gene play in disease severity?

The researchers made another interesting discovery. They found that mice infected with viruses missing the ORF8 gene were sicker than mice with the original strain of SARS-CoV-2, and the mice had increased inflammation in their lungs when compared with the original SARS-CoV-2 strain. The study concluded that the ORF8 seems to control the immune response in the lungs. 

Dr Frieman said that by inhibiting the immune response, ORF8 helps the virus replicate more in the lungs. This worsens infection. When OR58 was removed, it allowed the immune system to fight back harder.

Why is the gamma variant weaker than other strains?

After this, the researchers tried to find out how important the spike protein was for disease severity in each of the different variants of SARS-CoV-2. The researchers took the original virus and swapped out the spike gene with that of either the alpha, beta, gamma, or delta variant. 

Then, they infected cells and mice and observed how each of these viruses replicated and entered healthy cells. SARS-CoV-2 uses the spike protein to bind to the host's ACE2 receptors found on the outside of the cells lining the lungs as a way to get inside and infect cells. 

The study found that the spike protein determines the severity of disease caused by some of the variants, but not for others. The ability of the gamma variant to replicate and infect was less than that of the other variants. 

According to the researchers, the mutations in genes outside the spike, particularly in the ORF8 gene, could have played a role in making the gamma variant weaker than others. The gamma variant circulated in Brazil. However, it did not spread further around the globe as it was overtaken by stronger variants. 

The study concluded that accessory protein mutations could play an important role in the severity of Covid-19.