Insights Into Never-Before Characterized Mechanism of Immune Activation Could Pave Way for Anti-COVID-19 Therapies

Insights into a never-before characterized mechanism of immune activation and how a coronavirus enzyme disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host, could pave the way for anti-COVID-19 therapies.

Researchers from Cleveland Clinic’s Florida Research and Innovation Center (FRIC; Cleveland, Ohio, USA) have discovered that a coronavirus enzyme called PLpro (papain-like protease) blocks the body’s immune response to the infection. More research is necessary, but their findings suggest that therapeutics that inhibit the enzyme may help treat COVID-19.


One of the body’s frontline immune defenses is a class of receptor proteins, including one called MDA5, that identify invaders by foreign patterns in their genetic material. When the receptors recognize a foreign pattern, they become activated and kick-start the immune system into antiviral mode. This is done in part by increasing the downstream expression of proteins encoded by interferon-stimulated genes (ISGs).

In their study, the researchers identified a novel mechanism that leads to MDA5 activation during virus infection. They found that ISG15 must physically bind to specific regions in the MDA5 receptor - a process termed ISGylation - in order for MDA5 to effectively activate and unleash antiviral actors against invaders. They showed that ISGylation helps to promote the formation of larger MDA5 protein complexes, which ultimately results in a more robust immune response against a range of viruses. The research team has shown that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process.

“SARS-CoV-2 – the virus that causes COVID-19 – has evolved quickly against many of the body’s well-known defense mechanisms,” said FRIC scientific director Michaela Gack, Ph.D. “Our findings, however, offer insights into a never-before characterized mechanism of immune activation and how PLpro disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host. We discovered that inhibiting PLpro may help rescue the early immune response that is key to limiting viral replication and spread.”

“We’re already looking forward to the next phase of study to investigate whether blocking PLpro’s enzymatic function, or its interaction with MDA5, will help strengthen the human immune response against the virus,” added Gack. “If so, PLpro would certainly be an attractive target for future anti-COVID-19 therapeutics.”


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