Interfering with Interferon: Coronavirus Protein Hinders Key Antiviral Pathway

A group of immunologists who have been studying coronaviruses for over a decade have reported new insights into how coronaviruses interrupt a key antiviral pathway. The findings could lead to a new therapeutic route for COVID-19 that would also likely be applicable to future coronavirus outbreaks.

Led by Dr. Nigel Stevenson, Assistant Professor in Viral Immunology at Trinity College, the group discovered that SARS and MERS proteins block the generation of antiviral proteins, preventing the body from mounting a strong innate immune response against infection.

Both SERS and MERS—which emerged in 2002 and 2012, respectively—had higher fatality rates than COVID-19, but infected far fewer people. SERS killed 10% of the approximately 10,000 people who contracted the disease. Though MERS infected just 3,000, it had a fatality rate of about 40%.

Although distinct viruses, SERS and MERS bear many similarities to SARS-COV-2, the virus that causes  COVID-19. Understanding how SERS and MERS impede immune response could reveal new therapeutic options for COVID-19 and future coronavirus outbreaks yet to emerge.

Under normal circumstances, the interferon antiviral pathway activates a cascade of responses in human cells to produce hundreds of antiviral proteins that block viral replication. Therapeutic Interferon is used to fight certain infections, but it has never proved very effective against coronaviruses. The team’s findings, published recently in the journal Viruses, provides a potential explanation why.

“Over time, humans have evolved to fight viral infections by producing molecules called Interferons,” says Stevenson. “When a virus is encountered Interferons are produced, which, in turn, activates an antiviral pathway in our cells that is at the heart of our immediate immune response. The pathway produces specific proteins that switch hundreds of our anti-viral genes on. These genes then produce lots of different antiviral proteins that attack—and in most cases—kill the virus. In doing so, Interferons ‘interfere’ with a virus’ life cycle.”

The Dublin-based team discovered that SARS and MERS viruses have proteins that essentially throw a wrench in the works of this antiviral pathway. “[V]iruses have also evolved over time to suppress and avoid our immune system responses,” Stevenson says. “And our research aims to understand how viruses suppress the response to Interferons. Our current research has discovered that SARS and MERS prevent key proteins from being activated and entering the nucleus in our cells. The nucleus is where our DNA is stored and where genes are switched on, to generate a proper immune response.”

The team hopes that a drug can be developed that inhibits the ability of coronaviruses to suppress the Interferon pathway. “If we could restore the natural ability of our immune systems to fight viral infection and prevent viral replication, we could treat infected people with much greater success,” Stevenson says.

Given the similarity in coronaviruses and their modes of action, such a drug would likely prove effective against all the deadly coronaviruses, he adds.