New Delhi: The SARS-CoV-2 virus has a way of shielding itself inside the body while replicating and spreading, helping it stay intact and infectious.
Researchers at the Texas Biomedical Research Institute and the University of Chicago have uncovered the mechanism that enables this. Their findings, published in Nature Communications, show that without this protective mechanism, the virus’s ability to infect cells is significantly reduced.
The discovery offers a potential target for new Covid-19 therapies and provides insights that could inform future vaccine and antiviral development. The study builds on earlier work from Texas Biomed that identified viral proteins most important for the virus’s pathogenicity, or its ability to cause disease.
“In 2021, we found that the accessory protein ORF3a is one of the most important proteins for the virus and when we knock it out, the virus becomes much less harmful – but we didn’t know why,” said Texas Biomed Staff Scientist Chengjin Ye, Ph.D. “Now, working together with our collaborators at University of Chicago, we understand the mechanism.”
The research shows that SARS-CoV-2 ORF3a plays a key role in protecting structural proteins, especially the spike protein, which allows the virus to infect other cells, as they are assembled on the surface of new viral particles.
It does this by driving the formation of a dense group of proteins that surround the spike protein and provide protection while in transit.
“It’s much like security detail protecting a person or an armored vehicle carrying cash to the bank,” the researchers explained.
The team in Chicago, led by Assistant Professor Jueqi Chen, Ph.D., termed these protective protein complexes “3a dense bodies” or 3DBs.
“It appears that 3DBs help prevent the spike protein from being cut into smaller components,” said Dr. Chen. “When ORF3a is missing, these 3DBs fail to form, and the spike protein often arrives damaged, severely impairing the nascent virus’s ability to infect new cells.”
“ORF3a could therefore be a good target for drugs to block the virus,” said Luis Martinez-Sobrido, Ph.D., Professor at Texas Biomed. “This discovery could also be instrumental for vaccine development, as we illustrated previously.”
The researchers also explored whether related coronaviruses use the same strategy. They found that 3DBs are formed by coronaviruses found in bats and pangolins.
However, SARS-CoV and coronaviruses from civets did not form 3DBs, which may partly explain why the 2003 SARS outbreak was less infectious.
Around 8,000 people were infected with SARS, compared to more than 770 million reported COVID-19 cases globally, according to the World Health Organization.
“After identifying the 3DB structures and pinpointing the ORF3a parts residues critical for 3DB assembly, we collaborated with Drs. Ye and Martinez-Sobrido to engineer an attenuated virus lacking the ability to form 3DB,” Dr. Chen said. “Coronaviruses have the largest genomes among RNA viruses and therefore the reverse genetics expertise of Drs. Ye and Martinez-Sobrido was critical for the functional studies of 3DB during infection.”
The researchers highlighted that this was a multidisciplinary effort, combining cellular biology and advanced microscopy from Dr. Chen’s team with virology and virus engineering expertise from Drs. Ye and Martinez-Sobrido.
