Following the emergence of SARS-CoV-2 in 2020 there are now seven different coronaviruses known to infect humans. Four of those are associated with generally harmless common respiratory infections, but the other three (SARS, SARS-CoV-2 and MERS) are much more dangerous.
Why some coronaviruses are relatively harmless while others are incredibly lethal is still a bit of a mystery. Some answers lie in the proteins each individual virus uses to enter human cells, but what exactly makes SARS-CoV-2 so severe in some people and innocuous in others is unclear.
An impressive new study led by researchers from UCLA is offering a novel hypothesis to explain SARS-CoV-2 severity. Using an AI-driven machine-learning system the researchers discovered SARS-CoV-2 is broken down into fragments in a human body, and this viral debris can uniquely resemble endogenous peptides that overstimulate the immune system. This may play a significant role in the strange variable severity of disease from person to person.
“The textbooks tell us that after the virus is destroyed, the sick host ‘wins,’ and different pieces of virus can be used to train the immune system for future recognition,” says corresponding author Gerald Wong.
But the story of a virus isn’t exactly as simple as that. After a virus is neutralized by the immune system it is rapidly broken down, or dissolved, into tiny fragments. It has generally been assumed this stage of viral degradation was innocuous, but recent research has suggested some of these smaller viral fragments could trigger innate immune responses that account for severe disease associated with hyper inflammation.
To investigate this idea in the context of COVID, the researchers tracked all the possible peptide combinations that could be created through the degradation of SARS-CoV-2 proteins. They used a machine-learning system to measure the pro-inflammatory characteristics of all these potential peptides and discovered several of these viral fragments closely resemble molecules our immune system uses to heighten inflammatory responses.
“We saw that the various forms of debris from the destroyed virus can reassemble into these biologically active ‘zombie’ complexes,” explains Wong. “It is interesting that the human peptide being imitated by the viral fragments has been implicated in rheumatoid arthritis, psoriasis and lupus, and that different aspects of COVID-19 are reminiscent of these autoimmune conditions.”
The researchers then directly compared these SARS-CoV-2 viral fragments to debris that comes from a more harmless common-cold-causing coronavirus (HCoV-OC43). The fragments were very different, and the OC43 debris was found to not at all stimulate the immune system in the same way as SARS-CoV-2.
Even more interestingly, the researchers looked at what kinds of gene expression were stimulated by these SARS-CoV-2 viral fragments. These novel peptides were found to trigger similar patterns of expression to the full virus.
“What’s astonishing about the gene expression result is there was no active infection used in our experiments,” Wong notes. “We did not even use the whole virus – rather only about 0.2% or 0.3% of it – but we found this incredible level of agreement that is highly suggestive.”
So these findings may somewhat account for why SARS-CoV-2 triggers more severe disease than its common-cold coronavirus counterparts. But the study can only speculate as to why the virus’s effects are so variable from person to person.
Here the researchers indicate the striking uniqueness in each individual person’s enzyme efficiency could likely account for why some people don’t even notice they have COVID, while others end up struggling in hospital. Essentially, each of us break down foreign particles differently, and these unique differences may be responsible for how mild our illness is.
“... proteolytic degradation of SARS-CoV-2 is likely to be heterogeneous, as individual hosts display distinctive patterns of enzyme efficiencies varying routinely by fourfold to 50-fold, with protein expression being 'noisy' even at the single cell level,” the researchers write in the new study. “That proteolytic degradation of SARS-CoV-2 is expected to be drastically different among hosts may explain why the infection outcomes of SARS-CoV-2 are so heterogeneous, ranging from asymptomatic hosts to fatalities.”
The idea that viral fragments can linger in the body and cause persistent longer-term health problems is still relatively new. Over the last few years there has been emerging evidence showing viral debris from influenza causing long-term lung disease in some people, for example. But what these findings actually mean for potential future treatments is still unknown.
Wong does speculate the possibility that diseases such as COVID could be treated by inhibiting the actions of certain enzymes that are responsible for breaking the virus down into its more harmful components. Of course, to get to that point there will need to be lots more work done to systematically study exactly how certain viral fragments are created.
The new study was published in PNAS.
Source: UCLA
