Researchers from Trinity College Dublin have discovered how two deadly coronaviruses (SARS1 and MERS) outsmart one of our most important antiviral defences by shutting down parts of the immune system. The findings help explain why certain therapies (using interferon) have performed poorly in past outbreaks and point towards new therapeutic strategies that could matter in future coronavirus emergencies, said the authors.
SARS (epidemic 2002-2003) was highly transmissible and had fatality rates of around 10 per cent, while MERS (epidemic 2012, with periodic outbreaks since), was less transmissible but had higher fatality rates, approaching 33 per cent. In comparison, SARS2 (the virus that causes Covid 19) was by far the most infectious coronavirus to date, but the death rates were much lower. Ongoing research remains badly needed, as it is highly likely that another deadly coronavirus will emerge in years to come.
The new study, published in the leading international journal Frontiers in Immunology, shows how SARS1 and MERS dampen our body’s immune response by preventing specific antiviral genes from being switched on. These genes would ordinarily produce battle-focused proteins that act to fight-off viral attacks.
“Our immune system uses proteins called ‘interferons’ as an early warning system against viruses and one of these, Interferon-alpha (IFN-?), switches on hundreds of key antiviral genes,” said senior author, Prof Nigel Stevenson, who leads the Viral Immunology Research Team in Trinity’s School of Immunology and Biochemistry.
“Doctors have successfully used IFN-? to treat infections such as hepatitis B and C, but in MERS and SARS1 patients, this approach was not effective. Our new study reveals why.”
The researchers found that specific viral proteins from MERS and SARS1 trigger production of another interferon type — interferon-lambda (IFN-?) — in lung epithelial cells. And while IFN-? normally helps defend barrier tissues like the lungs, in this case it sets off an unexpected chain reaction.
IFN-? increases levels of a regulatory protein called USP18, and this acts like a brake on the immune system.
“Indeed, the molecular crosstalk dampens the IFN-? response. When USP18 levels rise, IFN-? can no longer efficiently induce antiviral genes. In other words, the virus triggers one immune signal in order to shut down another, more powerful inhibitory one,” adds Prof Stevenson.
“Crucially, when we experimentally silenced USP18, the cells regained their responsiveness to IFN-?, indicating that USP18 is a key player in coronavirus immune evasion and pinpoints it as being a potential target for future therapies.” The Covid-19 pandemic demonstrated how quickly coronaviruses can reshape global health, economies, and daily life. Research like this deepens our understanding of the microscopic chess match between viruses and the immune system and by revealing the precise moves viruses use to evade detection, scientists can design counter-moves in advance, said the authors.
First author of the research, Dr Yamei Zhang, Trinity, said: “In practical terms, this work suggests that future antiviral treatments may need to prevent viruses from activating the body’s own immune brakes.
“Understanding how viruses disarm our immune defences can directly shape how we treat infections, how we prepare for future pandemics, and how we protect global health in the years ahead.”
