Researchers at the University of Maryland School of Medicine have identified how several SARS-CoV-2 genes affect disease severity, which could lead to new ways to develop future vaccines or develop new treatments. . Genes control the host’s immune system, contributing to the ferocity with which the body responds to a COVID-19 infection.
Although people generally think that the spike protein that forms the structural “crown” is the driving factor behind each new variant of COVID-19, research results also show that mutations in these other “accessory” genes also play a role. a role in disease progression. . For this reason, the researchers believe that these accessory proteins warrant further study, as their mutations may become increasingly important as new variants emerge.
Their findings were published on August 30, 2022 in PNAS.
Omicron’s BA.4 variant, which circulated earlier this year, has been overtaken by the latest BA.5 variant of the virus currently circulating. Both of these variants appear to evade the immune system due to mutations in the spike protein. Because of these spike mutations, researchers say previous vaccines aren’t as effective at preventing the disease.
“What’s interesting is that the BA.4 and BA.5 variants have the same genetic sequence for the spike protein,” said Matthew Frieman, PhDAlicia and Yaya Foundation Professor of Viral Pathogen Research in the Department of Microbiology and Immunology at UMSOM. “This means that it is the other genes, the non-spike protein genes, that seem to affect how the virus copies itself and causes disease. So mutations in these other accessory genes are what allowed variants like BA.5 to outperform earlier versions of the virus.
The SARS-CoV-2 virus has three types of genes – those involved in making more copies of the virus, those that make up the structure of the virus, and accessory genes that have other functions. For this new study, the researchers wanted to know the function of accessory genes. To do this, they recreated viruses that lacked each of the four accessory proteins, then infected mice with these new viruses or the original virus. Then they observed how each virus affected the mice.
Dr. Frieman’s team of researchers found that the virus lacking the ORF3a/b gene caused milder infections than the original SARS-CoV-2 virus. Mice with this virus strain lost less weight and had less virus in their lungs than mice infected with the original virus. These results indicated that the ORF3a/b gene likely plays a role in making more copies of the virus through viral replication or in blocking the immune response to infection. Further experiments suggested that ORF3a/ba does extra work in the virus by appearing to activate the body’s innate immune system, the first line of defense launched by the immune system, signaling that a foreign invader must be defeated.
In contrast, the researchers found that mice infected with a virus that lacked the ORF8 gene were sicker than mice with the original strain of SARS-CoV-2. These mice had increased lung inflammation compared to the original SARS-CoV-2 virus. The researchers said ORF8 appears to control the immune response in the lungs.
“By inhibiting the immune response, ORF8 helps the virus replicate more in the lungs, which makes the infection worse. Once removed, it allowed the immune system to fight back harder,” said Dr. Frieman.
Next, the researchers looked at the significance of the spike protein for disease severity in each of the different SARS-CoV-2 variants. They took the original virus and replaced the spike gene with the spike gene of the alpha, beta, gamma, or delta variant. Then they infected cells and mice and watched how each of these viruses replicated and entered healthy cells. The virus uses the spike protein to hitch a ride on host ACE2 receptors found on the outside of cells lining the lungs in order to get inside and infect the cells.
Dr. Frieman’s team found that the spike protein determines the severity of some of the variants, but not others. The gamma variant was weaker than other variants in its ability to replicate and infect. The researchers believe that mutations in genes outside of the “spike”, particularly in the ORF8 gene, appear to play a role in making this version weaker than the others. Although the gamma variant circulated in Brazil, it did not spread further around the world as it was overtaken by stronger variants.
“While spike mutations are important for enhancing receptor binding and entry into cells, researchers have also found that mutations in accessory proteins can alter the clinical presentation of disease,” said Mark T. Gladwin, MD, Vice President of Medical Affairs at the University of Maryland, Baltimore and Professor Emeritus John Z. and Akiko K. Bowers and Dean, UMSOM. “We need to learn more about the role of accessory protein mutations in COVID-19 infection, especially as new variants and subvariants continue to emerge where these other proteins may play a more important role. .”
The researchers plan to focus on dissecting more of ORF8 function in future studies.
Other UMSOM authors include graduate student Marisa McGrath, postdoc Carly Dillen, PhD, research technician Lauren Baracco, and postdoc Louis Taylor, PhD; the other study co-authors were from the J. Craig Venter Institute.
This work was supported by grants from the Bill and Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases (R01AI137365 and R03AI146632), and the J. Craig Venter Institute.
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