Researchers at the University of Maryland School of Medicine have identified how several genes in SARS-CoV-2 affect the severity of the disease, which could lead to new ways to develop future vaccines or develop newer treatments. The genes control the host’s immune system, contributing to how fiercely the body responds to a COVID-19 infection.
While people typically think of the spike protein that forms the structural “corona” as the driving factor for each new variant of COVID-19, the research results also show that mutations in these other “accessory” genes also play a role in disease progression. . Because of this, the researchers believe that these accessory proteins warrant further study, as their mutations may become increasingly significant as newer variants emerge.
Their findings were published on August 30, 2022 in PNAS.
Omicron’s BA.4 variant, which circulated earlier this year, was superseded by the latest BA.5 variant of the virus now circulating. Both variants appear to evade the immune system due to mutations in the spike protein. Because of these spike mutations, researchers say earlier vaccines are not as effective at preventing disease.
“What’s interesting is that both the BA.4 and BA.5 variants have the same genetic sequence for the spike protein,” said Matthew Frieman, PhD, Alicia and Yaya Foundation Professor of Viral Pathogen Research in the Department of Microbiology and Immunology of the UMSOM. . “That means it’s the other genes, the non-spike protein genes, that seem to affect the way the virus copies itself and causes disease. So it’s the mutations in these other accessory genes that have allowed it to variants such as BA.5 surpass previous 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 the virus structure, and accessory genes that have other functions. For this new study, the researchers wanted to find out the function of the accessory genes. To do this, they recreated viruses that lacked each of the four accessory proteins and then infected mice with either these new viruses or the original virus. They then looked at how each virus affected the mice.
The team of researchers of Dr. Frieman found that the virus that lacked the ORF3a/b gene caused milder infections than the original SARS-CoV-2 virus. Mice with this strain of virus lost less weight and had less virus in their lungs than mice infected with the original virus. These findings indicated that the ORF3a/b gene probably plays a role in making more copies of the virus through viral replication or blocking the immune response to infection. Other experiments suggested that ORF3a/b has an additional job in the virus because it appears 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.
Instead, the researchers found that mice infected with viruses that lacked the ORF8 gene were sicker than mice with the original strain of SARS-CoV-2. These mice had increased inflammation in their lungs compared to the original SARS-CoV-2 virus. ORF8 appears to control the immune response in the lungs, the researchers said.
“By inhibiting the immune response, ORF8 helps the virus replicate more in the lungs, which makes the infection worse. When it was removed, it allowed the immune system to fight harder,” said Dr. Frieman.
The researchers then analyzed the importance of the spike protein for disease severity in each of the different SARS-CoV-2 variants. They took the original virus and swapped the spike gene with the spike gene of the alpha, beta, gamma, or delta variant. They then infected cells and mice and observed how each of these viruses replicated and entered healthy cells. The virus uses the spike protein to hitchhike to the host’s ACE2 receptors on the outside of the cells lining the lungs as a way to enter and infect the cells.
The team of Dr. Frieman found that the spike protein determines the severity of some of the variants, but not others. The gamma variant was weaker than the other variants in its ability to replicate and infect. The researchers think that mutations in genes outside the “spot,” 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 worldwide as it was overtaken by stronger variants.
“While spike mutations are important for enhancing receptor binding and cell entry, the researchers also found that mutations in accessory proteins can alter the clinical presentation of the disease,” he said. Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore and the John Z. and Akiko K. Bowers Distinguished Professor 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 more of a leading role.”
The researchers plan to focus on further dissecting the function of ORF8 in future studies.
Other UMSOM authors include graduate student Marisa McGrath, postdoc Carly Dillen, PhD, research technician Lauren Baracco, and postdoc Louis Taylor, PhD; 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.
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was founded in 1807 as the first public medical school in the United States. It continues today as one of the world’s leading and fastest-growing biomedical research enterprises, with 46 departments, centers, institutes and academic programs and a faculty of more than 3,000 physicians, scientists and allied health professionals, including members . of the National Academy of Medicine and the National Academy of Sciences, and a two-time distinguished recipient of the Albert E. Lasker Award for Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide intensive research, academic and clinical care to nearly 2 millions of patients every year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments ranking highly among all medical schools in the country in research funding. As one of seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of more than $6 billion and an economic impact of nearly $20 billion on the state and local community . Ranked eighth among public medical schools in research productivity (as profiled by the Association of American Medical Colleges), the School of Medicine is an innovator in translational medicine, with 606 active patents and 52 emerging companies. In the latest US News & World Report ranking of the best medical schools, published in 2021, the UM School of Medicine is ranked #9 out of 92 public medical schools in the US and in the top 15% (No. 27) of all. 192 US public and private medical schools. The Faculty of Medicine works locally, nationally and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu
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