Unmasking the stealth virus behind COVID-19

Scientists have discovered the pandemic-causingcoronavirus is unique in short-circuiting the safest way our immune system kills off a virus, which could have implications for treating COVID-19 with interferon.

Interferon describes a family of proteins produced by the body's immune system in response to an invading viral infection. As the name implies, interferon interferes with the virus's ability to copy itself.

Interferon drugs are made in the lab and were used for years to treat hepatitis, a liver infection, as well as other diseases that involve the immune system, such as multiple sclerosis and some cancers.

In May, researchers in Hong Kong published the results of their Phase 2 trial on fewer than 150 people who were admitted to hospital with mild or moderate COVID-19. Participants were randomly assigned to a combination of potential antivirals, including interferon, or placebo injections for two weeks.

The findings lent support to the idea of continuing research efforts, including in Canada, to investigate interferon in larger, blinded trials designed to find more definitive answers.

Dr. Jordan Feld, a liver specialist at Toronto General Hospital and senior scientist at U of T, previously used interferon to treat people infected with hepatitis. He's now leading a Phase 2 clinical trial to test a targeted form of the drug, called peginterferon lambda, in injections compared with saline placebo injections.

"It's kind of like a stealth virus," Feld said of SARS-CoV-2, the virus that causes COVID-19.

Normally, when interferon in the body's white blood cells responds to a viral invader, the interferon sends out a flare signal so nearby cells will work to stop the virus from copying itself or replicating if they, too, should be invaded.

In experiments on ferrets infected in the lab (a common animal model for studying respiratory viruses) and healthy human lung cells, as well as in people with COVID-19, doctors and scientists say it seems like the natural interferon "flies under the radar" of the immune system and isn't activated the way it should be.

Feld said the idea behind giving interferon medications is toprovidethe body withwhat it should be making to fend off the infection.

The potential therapeutic approach gained scientific backing last month when a study published in the journal Cell showed a "striking" feature ofSARS-CoV-2 infection.

Ben tenOever is a Canadian-born professor of microbiology at the Icahn School of Medicine at Mount Sinai in New York who led the Cell studyand has been flooded with e-mail requests from researchers the world over to test experimental drug compounds against the virus.

TenOever said every cell that gets infected has two major jobs:

1. Fortify its defences and those around it with a "call to arms" mediated by interferon, like sending out an emergency flare for the immune system's first responders.
2. Send a "call for reinforcements" for a longer-term response by releasing proteins called chemokines.

Most viruses block both of those roles.

What makes SARS-Cov-2 unique is it blocks the call-to-arms functionfrom interferon only.

Reinforce call to arms with drug?

"Treatment with interferon or drugs that induce interferon, the main character in the call to arms, is probably beneficial," tenOever said.

"The secret is to do it early,"he said, when people have a mild cough and test positive for the virus and haven't developed respiratory distress.

But there could also be mild side-effects.

When fighting off a flu virus, blame interferon for feeling so crummy, feverish and achy as your immune system kicks into high gear.

Likewise, interferon drugscould also lead to flu-like symptoms for a day or two.

Individuals enrolling in COVID-19 clinical trials of interferon based in Toronto, Hamilton, Ont., Harvard in Cambridge, Mass., Stanford in California, Johns Hopkins in Baltimore and elsewhere will need to weigh whether that (potential) shortfall is worth the (potential) payoff of protection from the deadly damage and delivers key answers that only their participation can offer.

TenOever said what the enormous scientific interest in the publication shows is an incredible demand for biosafetyLevel 3 labs like his during the pandemic. Without that lab capacity, the fear is that medical researchers won't be able to run all the experiments they need to do to guide vaccine efforts.

Matthew Miller is an associate professor of infectious disease and immunology at McMaster University who isn't involved in the clinical trials or studies.

Miller said interferon is what cells use to try to kill off the virus by themselves.

"Its sort of the preferred route," Miller said, adding interferon is also the safest way for the body to get rid of a virus.

Miller called tenOever's paper "an important first step in understanding how our body is responding to this particular new virus."

Speed up recovery

Dr. Sarah Shalhoub, a transplant infectious disease physician at Western University's medical school, studied the use of interferon to treat another coronavirus infection called Middle East Respiratory Syndrome or MERS.

While interferon hasn't yet panned out to fight MERS, Shalhoub is optimistic for COVID-19.

"Patients that received interferon beta clear their viruses faster and the duration for hospital admission was also significantly lower," Shalhoub said of the Hong Kong findings last month.

"It was encouraging in that sense that there might be an effective therapy that's available on the market that can be repurposed."

Shalhoub was quick to add a caution. Since no one in either the drug or placebo group died, the mild infections and response to them are difficult to interpret without more research.