Most people infected with SARS-CoV-2 experience mild symptoms, but a small percentage can develop severe complications like respiratory failure, septic shock, and failure of multiple organs. Interestingly, COVID-19 can also affect organs that have not been attacked directly by the virus. Some patients with severe disease experience blood clotting and damaged blood vessels. Others can develop symptoms similar to autoimmune diseases, such as arthritis or lupus, with signs of activation of the immune system that are not typical for viral infection.
A new international study suggests that when the immune system breaks down (degrades) the virus, it leaves virus particles that can trigger harmful immune responses. The authors compare this process to food digestion which does not just end with breaking down the food but also leave food particles that have impacts on our metabolism.
Viral fragments mimic known human immune peptides
The researchers used state-of-the-art scientific methods to identify specific particles that are produced during the degradation of SARS-CoV-2 and could cause severe inflammation. These fragments are called xenoAMPs as they resemble known antimicrobial peptides called AMPs.
AMPs are part of our immune system and can kill bacteria, viruses, parasites and even cancerous cells.
The most famous AMP in our body is cathelicidin LL-37 and is responsible for immune defense against microbes. When a virus replicates in our cells, negatively charged molecules like double-stranded RNA (dsRNA) are generated. Cathelicidin LL-37 is positively charged and therefore binds this dsRNA. This forms a cathelicidin LL-37/dsRNA complex which stimulates the immune response and helps us fight infections. But: this stimulation can also lead to autoimmune reactions in people with a dysregulated immune system.
In this study, the researchers tested whether SARS-CoV-2 fragments behave similar to cathelicidin LL-37. First, to identify SARS-CoV-2 fragments, the study authors used machine learning tools to scan all proteins that are produced during the virus degradation. They focused on three protein fragments with a high positive charge, similar to cathelicidin LL-37.
SARS-CoV-2 is one virus type in the family of coronaviruses. To understand its specific impact, the researchers not only compared SARS-CoV-2 fragments with cathelicidin LL-37 but also with fragments from another human coronavirus called OC43 (HCoV-OC43), which causes only a mild common cold. They found that SARS-CoV-2 has more specific regions with high positive charge, which means that these particles are more likely to function like cathelicidin LL-37 and cause more severe inflammation than the less harmful HCoV-OC43.
The genome of SARS-CoV-2 contains xenoAmp motifs (source: Zhang et al.)
A new therapeutic target?
Finally, the researchers conducted a series of laboratory experiments to corroborate these findings. They performed mass spectroscopy on samples from 29 patients with severe COVID-19. The results showed the presence of both cathelicidin LL-37 and different SARS-CoV-2 fragments, some of which qualified as the above-mentioned xenoAMPs.
Further experiments demonstrated were performed in mice. They showed that these positively charged SARS-CoV-2 fragments could assemble with dsRNA, which provoked a stronger immune reaction than that observed with fragments from the less harmful HCoV-OC43. This was shown through the increased production of proinflammatory molecules in monocytes (a type of immune cells), skin and lung cells.
What does this study mean?
Altogether, this study suggests a novel and unexpected way in which SARS-CoV-2 can trigger intense immune responses in the body even after our immune system destroys the virus. This could explain the wide range of severe symptoms and complications seen in patients with COVID-19, including those similar to autoimmune diseases.
However, this study only shows that SARS-CoV-2 has more of the positively charged xenoAMPS than other coronaviruses. Finding out if and how theses motifs can be targeted will have to be subject of further work. Nevertheless, the researchers brought us one step further in understanding the pandemic. They hope that these findings will help find treatments and also help identify the potential pandemic threat of future coronaviruses.
