When Yamei Zhang peered into the cellular chaos triggered by MERS and SARS1, she wasn’t just studying viruses—she was uncovering a biological betrayal. At Trinity College Dublin, Zhang and her team discovered that these deadly coronaviruses hijack the body’s own defense system, flipping a hidden switch that silences a crucial antiviral alarm. This molecular sleight of hand explains why past attempts to treat such infections with interferon-alpha failed, and it reveals a precise target for future therapies that could outmaneuver the next deadly coronavirus before it gains ground.
Coronaviruses have long played a high-stakes game with human immunity. While SARS2—the virus behind the recent pandemic—spread with unmatched speed, its predecessors were far deadlier. SARS1, which emerged in 2002, carried a fatality rate of around 10%, while MERS, first identified in 2012, killed nearly one in three infected people. Both viruses, unlike SARS2, proved resistant to treatments involving interferon-alpha, a key signaling protein the immune system uses to rally antiviral defenses. For years, scientists puzzled over this resistance. Now, the Trinity team has cracked the code.
Their study, published in Frontiers in Immunology, shows that proteins from MERS and SARS1 trigger lung cells to produce interferon-lambda. On its own, this protein helps protect mucosal barriers. But in this case, it sets off a dangerous cascade: interferon-lambda boosts levels of a regulatory protein called USP18, which acts as a brake on the immune system. With USP18 elevated, interferon-alpha can no longer activate the hundreds of antiviral genes needed to stop the virus in its tracks. "The virus triggers one immune signal in order to shut down another, more powerful one," explains Prof. Nigel Stevenson, who leads the Viral Immunology Research Team at Trinity. It’s a cunning exploitation of our own biology—using our defenses to disable us.
The breakthrough came when the researchers silenced USP18 in infected cells. Suddenly, the cells regained their sensitivity to interferon-alpha and resumed their antiviral response. This simple experiment confirmed USP18 as a linchpin in the virus’s evasion strategy and a promising target for future drugs. Rather than flooding the body with interferon—a tactic that failed in past outbreaks—therapies could instead block USP18, preventing the virus from slamming the brakes on immunity.
This discovery does more than explain past treatment failures; it arms scientists with a blueprint for future pandemic preparedness. As climate change and global travel increase the risk of emerging coronaviruses, understanding these molecular tricks becomes critical. "In practical terms, this work suggests that future antiviral treatments may need to prevent viruses from activating the body's own immune brakes," Zhang says. By turning the immune system’s vulnerabilities into strategic advantages, medicine may one day stay a step ahead of the next global threat.