Researchers at the University of California San Diego School of Medicine have discovered a way in which SARS-CoV-2, the coronavirus that causes COVID-19, hijacks the machinery of human cells to blunt the immune response, allowing it to establish infection, replicate and cause disease. .
In short, the virus genome is tagged with a special marker by a human enzyme that tells the immune system to pull out, while increasing the production of the surface proteins that SARS-CoV-2 uses as a “doorknob” to do. enter the cells.
The study, published on April 22, 2021 in Cell reports, helps lay the groundwork for new antiviral immunotherapies – treatments that work by boosting a patient’s immune system, rather than directly killing the virus.
“This virus is very smart to use host machines to simultaneously go into stealth mode and get into more cells,” said Tariq Rana, PhD, professor and head of the genetics division in the pediatrics department of the medical school. of UC San Diego. and Moores Cancer Center. “The more we know about how the virus takes hold in the body, the better equipped we are to disrupt it.”
In human cells, genes (DNA) are transcribed into RNA, which is then translated into proteins, the molecules that make up the majority of cells. But it’s not always that simple. Cells can chemically modify RNA to influence protein production. One of these modifications is the addition of methyl groups to adenosine, one of the building blocks of RNA. Known as N6-methyladenosine (m6A), this change is common in humans and other organisms, including viruses.
Unlike humans, the entire genomes of some viruses, including SARS-CoV-2, are made up of RNA instead of DNA. And rather than hauling the machines around to translate that into protein, the coronavirus is forcing human cells to do the job.
Rana and her team have already discovered that m6A plays an important role in HIV and Zika virus infections. In their latest study, the researchers found that the human enzyme METTL3 adds methyl groups to introduce m6A into SARS-CoV-2 RNA. This change prevents the virus’s RNA from triggering inflammatory molecules called cytokines. To the team’s surprise, METTL3 activity also led to increased expression of pro-viral genes – those that code for proteins necessary for SARS-CoV-2 replication and survival, such as ACE2, the cell surface receptor that the virus uses to enter human cells. .
“It remains to be seen why our cells are helping the virus like this,” Rana said.
When the team removed METTL3 from cells in the lab, using gene silencing or other methods, they saw the opposite: a pro-inflammatory molecule known as RIG1 binds to viral RNA, plus inflammatory cytokines were produced and pro-viral genes were inhibited. . Ultimately, inhibition of METTL3 suppressed viral replication.
To see how this mechanism plays out in the real world, the team compared post-mortem lung samples from COVID-19 patients and healthy lung biopsies. In patients who died from severe COVID-19, the team found that METTL3 expression was lower and inflammatory genes were elevated. This makes sense in the later stages of COVID-19, Rana said, because the cytokine storm – the excessive activation of the patient’s immune system – is known to make the disease worse.
“It’s like there are two phases of infection – in the first the virus needs METTL3 to help it escape the immune response,” he said, “but in the second phase, once the virus replicates like crazy, it is best to down-regulate METTL3. “
Rana’s team is currently validating their findings in animal models and developing METTL3 inhibitors to test as potential experimental therapies for COVID-19.
“We hope that by manipulating the levels of m6A in the virus, we might be able to time the innate immune response in a way that benefits patients with COVID19, especially for mild or moderate patients who have no not developed a cytokine storm, ”Rana said. “The challenge is that cells have many other enzymes like METTL3, known as methyltransferases, so the inhibition would have to be done very specifically, at a specific time.”
Study co-authors include: Na Li, Hui Hui, Bill Bray, Rob Knight, Davey Smith, Aaron F. Carlin, UC San Diego; Gwendolyn Michelle Gonzalez, Yinsheng Wang, UC Riverside; Mark Zeller, Kristian G. Anderson, Scripps Research.
Disclosure: Tariq Rana is a founder of ViRx Pharmaceuticals and owns a stake in the company. The terms of this agreement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.