Healthy cellular protein production (left column), compared to how SARS-CoV-2 disrupts these processes (right column). (Credit: Inna-Marie Strazhnik)
New research determines how virus breaks in & suppresses normal defense mechanism
With more than six months’ experience observing and studying COVID-19 infection, physicians and researchers now have a good understanding of the disease’s symptoms, but lack knowledge about what SARS-CoV-2, the virus that causes COVID-19, is doing inside human cells to make people so sick.
New research, published by scientists at the University of Vermont (UVM) and Caltech in the journal Cell, has pinpointed three specific mechanisms that allow SARS-CoV-2 to incapacitate human cells by disabling the cell’s alarm system to call for help or warn nearby cells of infection. This new information provides insights into how to fight the virus.
A virus like SARS-CoV-2 breaks into a human cell and hijacks the cell’s resources and machinery to spread. To be successful, a virus needs to effectively evade a cell’s defenses, but not kill it, because it requires the host cell to live. Human and mammalian cells have built-in defense mechanisms to deal with viral infections: when viral genetic material is detected, this triggers a cascade of events – including the release of interferon – designed to shut down the infection and notify neighboring cells of the threat.
Researchers have found that patients with severe COVID-19 symptoms show low levels of interferon response. This information led researchers to investigate how the virus suppresses these normal defense mechanisms.
Together, co-corresponding authors Dev Majumdar, Ph.D., assistant professor of surgery at UVM’s Larner College of Medicine, and Mitchell Guttman, Ph.D., professor of biology at Caltech and a Heritage Medical Research Institute investigator, with assistance from Jason Botten, Ph.D., professor of medicine, who studied SARS-CoV-2 in UVM’s BSL-3 facility, examined each of the roughly 30 viral proteins in SARS-CoV-2 and mapped out how they interact with host human cells within a lab dish. They found that SARS-CoV-2 proteins attack three critical cellular processes to disrupt cellular communication.
“Each viral protein is like a Swiss army knife, with breathtaking capabilities to gum up the works in a cell and make sure the virus can successfully get through another round of infection,” says Majumdar. “This work was the first to show that three ‘normal functions’ of the cell – translation by ribosomes, splicing by spliceosomes, and trafficking of proteins around the cell – are really thrown into chaos by the virus.”
“Viruses are amazing,” says co-first author Emily Bruce, Ph.D., a faculty scientist who worked at UVM’s BSL-3 facility. “Viruses and cells are continually in an evolutionary arms race to outwit one another. SARS-CoV-2 has evolved intricate and specific ways to disable cells without killing them outright, so that the virus can still use the cell for its own purposes.”
The cell’s nucleus houses its genetic material – DNA. This so-called genome functions like a comprehensive instruction manual, with “chapters” on “How to Send a Signal” or “What to Do in Case of Viral Infection,” for example. The rest of the cell contains the machinery that creates the proteins (such as interferon) that carry out these instructions.
The first step of this process is transcription, through which a piece of DNA in the cell’s nucleus is read and copied into a molecule (called mRNA) that can leave the nucleus and travel to the rest of the cell. Before exporting out of the nucleus, mRNA is often re-assembled and “matured” in a process called splicing, where intervening sequences called introns are systematically removed.
Next, after export out of the nucleus, a piece of cellular machinery called the ribosome attaches to the mature mRNA, reads it, and builds the appropriate corresponding protein through a process called translation. Some proteins are designed to move outside the cell of origin to transmit messages to other cells, like a warning about the presence of a viral infection. In this situation, another piece of cellular machinery, called signal recognition particle, comes into play; it works like a transport system that helps proteins move from inside to outside a cell.
Majumdar’s lab discovered that SARS-CoV-2 proteins interfere with this whole process at multiple stages. Some of the virus’s proteins prevent RNA from being full assembled and spliced. Others plug up the ribosome so that it cannot form new proteins. Other SARS-CoV-2 proteins interfere with the signal recognition particle and protein transport.
The researchers found that NSP1, the protein that plugs up the ribosome, blocks human mRNA from entering the ribosome but allows viral mRNA to pass through. Viral mRNA contains a genetic signature that acts like an access code that effectively hijacks the ribosome to make viral proteins but not human proteins.
"We understand so little about this virus compared to HIV or influenza,” says Majumdar. “I’m looking forward to more basic science work so we can get a first draft of how this virus replicates and takes over the cell. Armed with that kind of information, we can think meaningfully about targeted therapeutics, monoclonals, and vaccines."
(Contributors to this news release include Lori Dajose at Caltech and Dev Majumdar at UVM.)