"Zombie" COVID-19 fragments linger for some, causing severe disease outcomes, new research reveals

Though the COVID-19 pandemic has largely faded from the public mind, infections are still very common and not always benign like the flu. There is a link between inflammation, the immune system and COVID-19 that is not yet quite understood — and it could still be causing thousands of deaths and disabilities. 

As Salon has previously reported, severe cases of COVID can trigger a hyperinflammatory response called a "cytokine storm" so intense that it seems to exhaust the T cells critical to immune function and decrease their number. There has been evidence to suggest this can impact the immune system's ability to fight future infections from both COVID-19 and other diseases as well. More recently, researchers found that the inflammation caused by COVID-19 in pregnant women led to an inflammatory response in their infants causing respiratory distress after birth.

There is something specific about a SARS-CoV-2 infection, the virus that causes COVID, and how it can sometimes lead to an overactive immune response. Yet the way in which this occurs remains a mystery.

But now, researchers at the University of California-Los Angeles say they are one step closer to understanding how COVID-19 can result sometimes in severe outcomes or death while other coronaviruses like the common colds don’t. The answer, they believe, lies in so-called “zombie” virus fragments that linger and cause inflammation long after the virus has been destroyed. 

“There's a kind of biomimicry going on here, that once the virus is broken down these pieces are actually active and they can assemble with double-stranded RNA that's commonly found in viral infections,” Gerard Wong, corresponding author and a professor in microbiology, immunology and molecular genetics at the University of California-Los Angeles, told Salon in an interview. “And, that’s the zombie part — after you destroy this virus that should be dead, it's not. It actually can reassemble into these complexes that can have very strong immune activation ability.”

As Wong alluded to, once a virus interacts with the human immune system, the virus is usually broken down to a point where the host and its immune system wins. As a result, the immune system learns from that interaction and builds immunity to that virus by knowing exactly how to defeat it next time. But it doesn’t exactly work that way with SARS-CoV-2.

Want more health and science stories in your inbox? Subscribe to Salon's weekly newsletter Lab Notes.

As shown in their study that will be published in the journal Proceedings of the National Academy of Sciences this week, it’s possible that a COVID-19 infection can turn the immune system against the body leading to catastrophic and sometimes fatal results — pattern that deviates from the standard trajectory of a viral infection and what scientists expect to see in immunology. 

To find this peculiar pattern with a COVID-19 infection, Wong and his colleagues developed an artificial intelligence system to scan a collection of proteins produced by a SARS-CoV-2 infection. After the scan, they performed a series of validation experiments, some of which used mice. Through the combination of the two methods, the researchers found that specific viral fragments lingered from a SARS-CoV-2 infection, broke down into pieces and mimicked immune peptides that are responsible for worsening immune responses. This suggested that more serious COVID-19 outcomes are a result of these leftover fragments that are essentially overstimulating the immune system. As a result, this is causing rampant inflammation in some people. 

Wong compared it to eating five croissants from a bakery. Once the croissants are digested, the impact of them is not — it’s possible that they could negatively affect cardiovascular health, for example. Of course, it doesn’t happen all the time for every COVID-19 infection. For some people, an infection is mild and symptoms don’t last long. But for others, it can lead to long COVID, in which symptoms last for months or never resolve. Wong said the reason the fragments linger and cause hyper-inflammation in some people and not others could be due to variation in enzymatic activity, which is the way in which proteins are broken down in the human body, which are varies from person to person. 

“I think the fact that we have such heterogeneous enzymatic activity amongst different hosts is one of the reasons that sometimes a person is unlucky enough to have the wrong fragment at the wrong place at the wrong time,” he said. “And that can mediate a lot of these types of effects.” 

Wong said this is the first of several papers that will look in-depth at this specific interaction and its potential outcomes. Long-term he hopes it can help possibly build a surveillance system that can help differentiate between harmful strains of SARS-CoV-2 and ones that are less severe based on how “molecular motifs” can amplify an immune response. He also hopes it can lead to better treatment opportunities for COVID-19. Currently, severe cases can be treated with antiviral medicine like Paxlovid.  

“Maybe the thing to do is to find ways of soaking up the viral fragments, assemble them into a form that is not pro-inflammatory and be able to enforce this detour in the immune system,” he said. “So that we don't have all of these outcomes.”