UMSOM researchers identify how multiple SARS-CoV-2 genes affect disease severity

UMSOM researchers identify how multiple SARS-CoV-2 genes affect disease severity Researchers at the University of Maryland School of Medicine have identified how multiple SARS-CoV-2 genes affect disease severity, which could lead to new ways to develop future vaccines or new treatments. Genes control the host’s immune system, which contributes to the severity of the body’s response to COVID-19 infection.

UMSOM researchers identify how multiple SARS-CoV-2 genes affect disease severity

Although the spiky protein that forms the structural ‘crown’ is generally thought to be the driving factor behind each new variant of COVID-19, the research findings also show that mutations in these other ‘extra’ genes also play a role. role in disease progression. For this reason, the researchers believe that these accessory proteins deserve further study, as their mutations may become increasingly important as new variants emerge.

Their findings were published August 30, 2022 in the journal PNAS.

Omicron’s BA.4 variant, which was circulated earlier this year, has been bypassed by the newest type of virus BA.5 currently circulating. Both of these variants appear to evade the immune system due to elevated protein mutations. Because of the high protein mutations, researchers say previous vaccines are not effective in preventing the disease.

Interestingly, both BA.4 and BA.5 variants have the same spike protein gene sequence. This means that it is the other genes, the non-prickly protein genes, that seem to influence how the virus copies itself and causes disease. So, it was the mutations in these other accessory genes that allowed variants such as BA.5 to replace previous versions of the virus. »

UMSOM researchers identify how multiple SARS-CoV-2 genes affect disease severity

Matthew Freeman, PhD, Alicia and Yaya Foundation Professor of Viral Pathogen Research, Department of Microbiology and Immunology, Amsom University.

The SARS-CoV-2 virus contains three types of genes: those that are involved in making more copies of the virus, those that make up the structure of the virus, and accessory genes that have other functions. In this new study, the researchers wanted to reveal the function of accessory genes. To do this, they reconstituted viruses lacking each of the four accessory proteins, and then infected mice with these new viruses, or the original virus. Then they observed how each virus affected the mice.

Dr. Freeman’s team of researchers found that a virus lacking the ORF3a/b gene caused a milder infection than the original SARS-CoV-2 virus. Mice infected with this strain lost less weight and had less virus in their lungs than mice infected with the original virus. These results suggest that the ORF3a/b gene may play a role in making more virus copies through virus replication or in preventing the immune response to infection. Other experiments suggested that ORF3a/ba has an additional role in the virus by appearing to activate the body’s innate immune system, the first line of defense launched by the immune system, indicating the necessity of defeating foreign invaders.

UMSOM researchers identify how multiple SARS-CoV-2 genes affect disease severity

In contrast, the researchers found that mice infected with a virus lacking the ORF8 gene were sicker than mice carrying the original SARS-CoV-2 strain. These mice had increased inflammation in their lungs compared to the original SARS-CoV-2 virus. The researchers said that ORF8 appears to control the immune response in the lungs.

“By inhibiting the immune response, ORF8 helps the virus to multiply more in the lungs, making the infection worse. When removed, it allowed the immune system to defend itself more,” Dr. Freeman said.

Next, the researchers looked at the significance of the spike protein to 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 for 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. The virus uses the spike protein to bind to the host’s ACE2 receptor, which is located on the outside of cells lining the lungs, in order to enter and infect cells.

Dr. Freeman’s team found that the spike protein determines the severity of some variants, but not others. The gamma variable was weaker than the other variables in its ability to reproduce and infect. The researchers believe that mutations in genes outside the “spike,” particularly in the ORF8 gene, appear to play a role in making this copy weaker than the others. Although the gamma variant circulated in Brazil, it did not spread further around the world as it was overtaken by the stronger variants.

said Mark T. Gladwin, vice president for medical affairs at the University of Maryland, Baltimore, and Professor Emeritus and Dean of UMSOM, John Z. and Akiko K. Bowers. “We need to learn more about the role of additional 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 the anatomy of ORF8’s function in future studies.

Other UMSOM authors are graduate student Marissa McGrath, postdoc Carly Dillen, Ph.D., research technician Lauren Baracco, and postdoc Lewis Taylor; The other study 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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