An in-depth study of how a novel coronavirus infects a cell has revealed that, unlike other known viruses, the novel coronavirus orchestrated a malicious takeover of a cell’s genes that produced what one leading scientist called “unique” and “unusual” changes.
Recent research has shown that viruses change the way DNA fragments are read in order to control genes that invade human cells, which may explain why older people are more likely to die of covid-19, and why antiviral drugs can not only save lives, but also prevent serious illness if taken before infection.
Benjamin tenOever, a virologist at the Icahn School of Medicine at Mount Sinai, said of how the sars-cov-2 virus that causes covid-19 hijacked the cell genome, “this is something I’ve never seen in my 20 years of working with viruses.”
He and his colleagues saw how sars-cov-2 blocked one set of virus-fighting genes but allowed another to turn on, a pattern never seen in other viruses.
For example, influenza and the original SARS virus (in the early 2000s) interfere with two branches of the body’s immune response — the “fight signal” gene and the “call for help” gene, as tenOever calls them.
The first group of genes produces interferon.The proteins released by the infected cells are biological signals that signal neighboring cells to activate about 500 of their own genes, slowing the virus’s ability to replicate.
This can last seven to 10 days, controlling virus replication and buying time for a second set of genes to act, tenOever said.
This second set of genes produces their own secreted proteins, called chemokines, which emit a biochemical “come here!”The alarm.When distant B cells that produce antibodies and T cells that kill viruses sense the alarm, they run to the source of the alarm.
If all goes well, the first set of genes could isolate the virus long enough for a deadly hitman to arrive and begin destroying it.
“Most other viruses interfere in some way with the fight genes and the help-seeking genes,” tenOever said.
“If they don’t, no one will get a viral disease,” a “one-two punch” that will knock out any initial infection.
However, he and his colleagues reported in a study published last week in the journal Cell that sars-cov-2 was uniquely able to block one type of cellular defense but activate another.
They studied healthy human lung cells grown in laboratory dishes, ferrets (which are susceptible to viruses) and lung cells from patients with covid-19.
In all three viruses, they found that within three days of infection, the virus induced the production of cytokines by the cell’s “help signal” gene.But it blocks their “fight signal” gene, interferon, which inhibits viral replication.
Instead of essentially preventing the virus from replicating, the result was a storm of inflammatory molecules in the lungs that tenOever called sars-cov-2’s “unique” and “abnormal” consequences for manipulating the target genome.
In another new study, Japanese scientists last week determined how sars-cov-2 was genetically manipulated.
Kei Sato of the university of Tokyo and his colleagues found that its ORF3b gene produces a protein called a transcription factor that has a “strong anti-interferon activity” that is stronger than the original SARS or flu viruses.The protein basically prevents cells from recognizing the presence of the virus in a way that blocks interferon gene expression.
In fact, the icahn team found no interferon in lung cells from patients with covid-19.Without interferon, tenOever says, “there’s nothing to stop the virus from replicating and festering forever in the lungs.”
This causes lung cells to release more “help-seeking” genes, calling out more and more immune cells.
Now, the lungs are full of macrophages, neutrophils and other immune cells, leading to this uncontrolled inflammation, tenOever said. “you start to have inflammation, which leads to more inflammation.”
At the same time, unchecked viral replication kills the lung cells involved in the oxygen exchange.”All of a sudden you’re in the hospital and you’re having trouble breathing,” he said.
Even before the novel coronavirus arrived, the “fight” part of the immune system was weaker in older people, as well as in people with diabetes, heart disease and other underlying diseases, than in younger, healthier people.
This further reduces the cells’ ability to inhibit viral replication with interferon, and causes the immune system to get out of balance in the direction of a dangerous inflammatory response.
The discovery that sars-cov-2 strongly inhibits interferon production in infected cells raises an interesting possibility: taking interferon may prevent severe covid-19, or even prevent it in the first place, said Vineet Menachery of the university of Texas medical branch.
In a study of human cells growing in laboratory dishes, he and his colleagues also found that sars-cov-2 “blocked the activation of a large number” of the interferon gene.
But when cells grown in a laboratory dish were given interferon ifn-1 before being exposed to a novel coronavirus, “the virus was difficult to replicate.”
After a few days, the number of viruses in infected cells treated with interferon was 1,000 to 10,000 times lower than in infected cells not treated with interferon.(the original SARS virus, by contrast, was insensitive to interferon.)
An effective vaccine to prevent infections and antiviral drugs like remdesivir to treat serious illnesses is believed to be needed to end the pandemic and prevent its return, but genetic research suggests a third strategy: prophylactic drugs.
Treatment with so-called type 1 interferon may “stop the virus before it forms,” Menachery said.
Giving drugs to healthy people is always a risky business, because all drugs have side effects.
“Interferon therapy has many complications,” Menachery warns.Various interferons used to treat hepatitis, cancer and many other diseases can cause flu-like symptoms.
Interferon “alerts the cell that the virus is coming,” Menachery said, so the pretreatment could “make the treated cell better able to resist the virus and limit its spread.”
Of course, this will require clinical trials, which are currently under way.